2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one derivatives and related compounds as c5a receptor modulators for treating vasculitis and inflammatory diseases

ABSTRACT

The present invention relates to derivatives of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein Ring A, X, Y, Z, R A , R 1 , R 2 , R 3  and R 4  are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as C5a receptor modulators.

The present invention relates to novel C5a receptor modulators offormula (I) and their use as pharmaceuticals. The invention alsoconcerns related aspects including processes for the preparation of thecompounds, pharmaceutical compositions containing one or more compoundsof formula (I), and their use as C5a receptor modulators, especially inthe treatment of vasculitic diseases or disorders, inflammatory diseasesor disorders involving intravascular microvesicle release, immunecomplex (IC) diseases or disorders, neurodegenerative diseases ordisorders, complement related inflammatory diseases or disorders,bullous diseases or disorders, diseases or disorders related to ischemiaand/or ischemic reperfusion injury, inflammatory bowel diseases ordisorders, and autoimmune diseases or disorders; as well as in contactsensitivity or an inflammation caused by contact with artificialsurfaces; increased leukocyte and platelet activation (and infiltrationto tissues thereof); pathologic sequelae associated to an intoxicationor an injury such as a trauma, an hemorrhage, a shock, or surgeryincluding transplantation, such sequelae including multiple organfailure (MOF), septic shock, shock due to intoxication, or acute lunginflammatory injury; pathologic sequelae associated withinsulin-dependent diabetes mellitus; myocardial infarction orthrombosis; edema or an increased capillary permeability; reduction ofcoronary endothelial dysfunction induced by cardiopulmonary bypassand/or cardioplegia; or cancer.

C5aR1 (CD88) is a seven transmembrane bound G protein coupled receptor(GPCR) belonging to the rhodopsin like family, the gene of which islocated on chromosome 19. It couples to pertussis toxin sensitiveGialpha2, Gialpha3 or pertussis toxin insensitive Galpha16 and initiatesseveral downstream signaling pathways. C5aR1 is expressed on a number ofimmune cell types including monocytes, neutrophils, mast cells,basophils and eosinophils. In addition, it is expressed on many othercell types including hepatocytes, pulmonary and endothelial cells,microglia, neurons and renal glomerular cells. There are a number ofligands described which bind to the C5aR. These include C5a, C5adesArgand C5a+1 kDa. C5a is a central effector molecule of the complementsystem which itself is a complex enzymatic cascade evolved to cruciallycomplement the immune system against invading pathogens, however, asignificant body of evidence shows that inadvertent complementactivation leads to many acute inflammatory disorders and autoimmunediseases (Ricklin, D., et al. (2010) “Complement: a key system forimmune surveillance and homeostasis.” Nat Immunol 11(9): 785-797) andspecifically C5a has been shown to be elevated in a number of theseinflammatory and autoimmune disorders. The complement system isactivated through four pathways: The classical pathway, and the mannosebinding lectin (MBL) pathway which is similar to the classical pathwayexcept for the initial recognition and activation steps which recognizepathogens or antibody complexes. The alternative pathway is activated bybinding of spontaneously activated complement C3 protein (C3b fragment)to pathogen surface. These three pathways all lead to the eventualformation of C3 convertases, which is the point where the 3 pathwaysconverge (Guo, R. F. and P. A. Ward (2005) Annu Rev Immunol 23:821-852). Subsequently C3 convertases lead to the formation of theanaphalatoxins C3a and C5a, together with other complement proteinsrequired to produce the membrane attack complex. A fourth pathway, theextrinsic pathway involves plasma proteases (eg. elastase, thrombin)which act directly on C3 or C5 leading to the subsequent production ofC3a and C5a. The anaphylatoxin C5a leads to the recruitment andactivation of inflammatory cells of the innate and adaptive system,partly through the enhancement of cell adhesion molecule expression, therelease of granule-based enzymes, delayed or enhanced apoptosis,phagocytosis, oxidative burst, histamine secretion and release andchemotaxis. In addition, it elicits the release of other proinflammatory mediators, such as TNF-a, IL-1, IL-6, IL-8, prostaglandins,and leukotrienes) (N. S. Merle et al. (2015) “Complement System Part II:Role in Immunity.” Front Immunol 6: 257), activation of endothelialcells and vascular permeability which may lead to events in which at theend thrombotic microangiopathy can occur. Therefore, C5a represents oneof the most potent inflammatory molecules produced during immuneresponses and because of its fundamental biology it is potentiallyimplicated in a very wide range of pathologies (Janeway's Immunobiology,8^(th) edition (2012), Kenneth Murphy, Garland Science, p. 48-72).

C5a is central to the immune system and as such is important in keyaspects of inflammation and tissue injury. In addition, there isconsiderable experimental evidence in the literature that implicatesincreased levels of C5a with a number of diseases and disorders, inparticular in autoimmune and inflammatory diseases and disorders(Ricklin, D., et al. (2010) Nat Immunol 11(9): 785-797).

There is a large body of evidence about C5a and its receptor C5aR incontributing to vasculitic diseases, which demonstrate that C5a levelsare elevated and give rise to leukocyte migration and subsequentinflammation which then leads to the eventual destruction of vesselwalls (Charles J., et al (2013) Semin Nephrol 33(6): 557-564;Vasculitis, 2^(nd) Edition (2008), Edited by Ball and Bridges, OxfordUniversity Press, pp 47-53; Huang, Y. M., et al. (2015) ArthritisRheumatol 67(10): 2780-2790; Kallenberg, C. G. and P. Heeringa (2015)Mol Immunol 68(1): 53-56). Inhibition of the C5aR with a C5aR antagonistwas effective at ameliorated anti-myeloperoxidase (MPO)-induced NCGN inmice expressing the human C5a receptor (Xiao, H. et al (2014) J Am SocNephrol 25(2): 225-231) and was confirmed to be effective in a phase IItrial of patients with anti-neutrophil cytoplasmic antibody (ANCA)associated vasculitis (ClinicalTrials.gov Identifier NCT02222155).Therefore, a C5a antagonist may be useful to treat vasculitic diseasessuch as ANCA associated vasculitis, leukoclastic vasculitis, Wegener'sgranulomatosis, microscopic polyangiitis, Churg-Strauss syndrome,Henoch-Schönlein purpura, polyateritis nodosa, rapidly progressiveglomerulonephritis (RPGN), cryoglobulinaemia, giant cell arteritis(GCA), Behcet's disease and Takayasu's arteritis (TAK).

C5a is generated when human blood makes contact with artificialsurfaces, such as in cardiopulmonary bypass and hemodialysis proceduresfor instance on the artificial surface of the heart—lung machine inassociation with vascular surgery such as coronary artery bypassgrafting or heart valve replacement or on surfaces of a kidney dialysismachine (Howard, R. J., et al. (1988) Arch Surg 123(12): 1496-1501;Kirklin, J. K., et al. (1983) J Thorac Cardiovasc Surg 86(6): 845-857;Craddock, P. R., et al. (1977) J Clin Invest 60(1): 260-264; Craddock,P. R., et al. (1977) N Engl J Med 296(14): 769-774) or in associationwith contact with other artificial vessels or container surfaces (e.g.ventricular assist devices, artificial heart machines, transfusiontubing, blood storage bags, plasmapheresis, plateletpheresis, and thelike). As such C5aR antagonists could prove useful in preventingdeleterious consequences of contact sensitivity and/or inflammationcaused by contact with artificial surfaces. In addition, it may beuseful in treating inflammatory disorders involving intravascularmicrovesicle release such as for example thrombotic microangiopathy andsickle cell disease (Zecher, D., et al. (2014) Arterioscler Thromb VascBiol 34(2): 313-320). A C5aR antagonist could also prove useful incertain hemotological diseases which are associated with activation ofcoagulation and fibrinolytic systems, disseminated intravascularcoagulation (DIC), pernicious anemia, warm and cold autoimmune hemolyticanemia (AIHA), anti-phospholipid syndrome and its associatedcomplications, arterial and venous thrombosis, pregnancy complicationssuch as recurrent miscarriage and fetal death, preeclampsia, placentalinsufficiency, fetal growth restriction, cervical remodeling and pretermbirth, idiopathic thrombocytopenic purpura (ITP), atypical hemolyticuremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH) andallergic transfusion reactions. The C5-specific humanized antibody,eculizumab is approved for paroxysmal nocturnal hemoglobinuria andatypical haemolytic uraemic syndrome (aHUS) (Wong E K, Kavanagh D,Transl Res. (2015) 165(2):306-20) and has been shown to be efficaciousin renal transplant such as acute antibody-mediated kidney allograftrejection and cold agglutinin disease further supporting a potentialrole for C5aR antagonists in these diseases.

In myocardial ischemia-reperfusion injury C5a has been described to havean important function. Complement depletion reduced myocardial infarctsize in mice (Weisman, H. F., T. et al. (1990) Science 249(4965):146-151; De Hoog, V. C., et al. (2014) Cardiovasc Res 103(4): 521-529)and treatment with anti-C5a antibodies reduced injury in a rat model ofhindlimb ischemia-reperfusion (Bless, N. M., et al. (1999) Am J Physiol276(1 Pt 1): L57-63). Reperfusion injury during myocardial infarctionwas also markedly reduced in pigs that were re-treated with a monoclonalanti-C5a IgG (Amsterdam, E. A., et al. (1995) Am J Physiol 268(1 Pt 2):H448-457). A recombinant human C5aR antagonist reduces infarct size in aporcine model of surgical revascularization (Riley, R. D., et al. (2000)J Thorac Cardiovasc Surg 120(2): 350-358) providing evidence for theutility of a C5aR antagonist in these diseases. In addition, diseasesrelated to ischemia/reperfusion injury, such as those resulting fromtransplants, including solid organ transplant, where C5a has been shownto play an important role (Farrar, C. A. and S. H. Sacks (2014) CurrOpin Organ Transplant 19(1): 8-13), could benefit from a C5aR antagonistas could related syndromes such as ischemic reperfusion injury, ischemiccolitis and cardiac ischemia (Mueller, M., et al. (2013) Immunobiology218(9): 1131-1138).

Furthermore, diseases where complement plays a role such as coronarythrombosis (Distelmaier, K., et al. (2009) Thromb Haemost 102(3):564-572), vascular occlusion, post-surgical vascular reocclusion,atherosclerosis, traumatic central nervous system injury, arrhythmogeniccardiomyopathy (Mavroidis, M., et al. (2015) Basic Res Cardiol 110(3):27) and Gaucher disease (Pandey et al. (2017) Nature 543: 108-112) couldalso benefit from a C5aR antagonist. Thus, C5aR modulators may be usedpreventatively in a patient at risk for myocardial infarction orthrombosis (i.e. a patient who has one or more recognized risk factorsfor myocardial infarction or thrombosis, such as, but not limited to,obesity, smoking, high blood pressure, hypercholesterolemia, previous orgenetic history of myocardial infarction or thrombosis) in order reducethe risk of myocardial infarction or thrombosis.

C5a causes increased capillary permeability and edema, leukocyte andplatelet activation and infiltration to tissues, as well asbronchoconstriction (Sarma, J. V. and P. A. Ward (2012) Cell HealthCytoskelet 4: 73-82; Czermak, B. J., et al. (1998) J Leukoc Biol 64(1):40-48). Administration of an anti-C5a monoclonal antibody was shown toreduce cardiopulmonary bypass and cardioplegia-induced coronaryendothelial dysfunction (Tofukuji, M., et al. (1998) J Thorac CardiovascSurg 116(6): 1060-1068).

C5a and its receptor are also involved in the pathogenesis of acuterespiratory distress syndrome (ARDS) (Hammerschmidt, D. E., et al.(1980) Lancet 1(8175): 947-949), Chronic Obstructive Pulmonary Disorder(COPD) (Marc, M. M., et al. (2004) Am J Respir Cell Mol Biol 31(2):216-219), and multiple organ failure (MOF) (Huber-Lang, M., et al.(2001) “Role of C5a in multiorgan failure during sepsis.” J Immunol166(2): 1193-1199; Heideman, M. and T. E. Hugli (1984) J Trauma 24(12):1038-1043). C5a increases monocyte production of two importantproinflammatory cytokines TNF-α and IL-I which contribute to pathologyin these diseases. C5a has also been shown to play an important role inthe development of tissue injury, and particularly pulmonary injury, inanimal models of septic shock (Smedegard, G., et al. (1989) Am J Pathol135(3): 489-497; Unnewehr, H., et al. (2013) J Immunol 190(8):4215-4225). In sepsis models using rats, pigs and non-human primates,anti-C5a antibodies administered to the animals before treatment withendotoxin or E. coli resulted in decreased tissue injury, as well asdecreased production of IL-6 (Hopken, U., et al. (1996) Eur J Immunol26(5): 1103-1109; Stevens, J. H., et al. (1986) J Clin Invest 77(6):1812-1816). Inhibition of C5a with anti-C5a polyclonal antibodies hasbeen shown to significantly improve survival rates in a caecalligation/puncture model of sepsis in rats (Czermak, B. J., et al. (1999)Nat Med 5(7): 788-792). In the same sepsis model, anti-C5a antibodieswere shown to inhibit apoptosis of thymocytes (Guo, R. F., et al. (2000)J Clin Invest 106(10): 1271-1280). Anti-C5a antibodies were alsoprotective in a cobra venom factor model of lung injury in rats, and inimmune complex-induced lung injury (Mulligan, M. S., et al. (1996) JClin Invest 98(2): 503-512). The importance of C5a in immunecomplex-mediated lung injury was also shown in mouse (Bozic, C. R., etal. (1996) Science 273(5282): 1722-1725). Therefore, a C5aR antagonistcould be of benefit in many inflammatory disorders and relatedconditions including neutropenia, sepsis, septic shock, stroke,inflammation associated with severe burns (Hoesel, L. M., et al. (2007)J Immunol 178(12): 7902-7910), osteoarthritis (Yuan, G., et al. (2003)Chin Med J (Engl) 116(9): 1408-1412), as well as acute (adult)respiratory distress syndrome (ARDS), chronic pulmonary obstructivedisorder (COPD), bronchial asthma (Pandey, M. K. (2013) Curr AllergyAsthma Rep 13(6): 596-606), systemic inflammatory response syndrome(SIRS), tissue graft rejection, hyperacute rejection of transplantedorgans, and the like, and multiple organ dysfunction syndrome (MODS). Inaddition, C5aR antagonists may be beneficial in treating pathologicsequelae associated with insulin-dependent diabetes mellitus such asdiabetic kidney disease (Li, L., et al. (2015) Metabolism 64(5):597-610), diabetic retinopathy (Cheng, L., et al. (2013). InvestOphthalmol Vis Sci 54(13): 8191-8198), lupus nephropathy (Bao, L., etal. (2005) Eur J Immunol 35(8): 2496-2506), Heyman nephritis, membranousnephritis, and other forms of glomerulonephritis such as C3glomerulopathy including dense deposit disease (DDD) (Zhang et al., ClinJ Am Soc Nephrol (2014) 9: 1876-1882). Furthermore, the compoundeculizumab has been shown to have potential utility for the treatment ofneuromyelitis optica.

C5aR antagonists substantially reduced ovalbumin (OVA)-induced totalcell (60%), neutrophil (66%) and eosinophil (65%) influxes in lavagefluid sampling suggesting that C5aR blockage might represent a noveltherapeutic agent for reducing asthmatic outcomes (Staab, E. B., et al.(2014) Int Immunopharmacol 21(2): 293-300).

The complement system and in particular C5a contribute to thedevelopment of many bullous diseases among other things throughactivation of innate cells including mast cells and neutrophils (e.g.bullous pemphigoid, bullous acquisita, Pemphigus foliaceus and Pemphigusvulgaris). The detachment of epidermal basal keratinocytes from theunderlying basement membrane is thought to be caused by autoantibodiesto keratinocytes at the cutaneous basement membrane leading to blistersand a high influx of neutrophils in both the upper dermal layers andwithin the blister cavities. In experimental models a reduction ofneutrophils or absence of complement (total or C5-selective) can inhibitformation of sub-epidermal blisters (Heimbach, L., et al. (2011) J BiolChem 286(17): 15003-15009; Gammon, W. R. (1989) Immunol Ser 46:509-525). Recent evidence has emerged to suggest that inhibition of C5amay prove beneficial in the treatment of the skin disorder hidradenitissuppurativa where an antibody against human C5a was shown to improvepatient outcome in an open label phase II clinical trial. A C5a receptorantagonist may therefore be useful in bullous diseases.

Complement is believed to be important in inflammatory bowel disease(IBD) pathology and the C5aR is found to be expressed in the epithelialcells of the colon. (Cao, Q., et al. (2012) Am J Physiol Cell Physiol302(12): C1731-1740). In addition, pharmacological inhibition of C5aactivity by PMX205 a peptidic C5aR antagonist is efficacious inpreventing DSS-induced colitis, providing further evidence thattargeting CD88 in patients with IBD irritable bowel syndrome, ulcerativecolitis, Crohn's disease, inflammatory bowel disease (IBD) (Johswich,K., et al. (2009) Inflamm Bowel Dis 15(12): 1812-1823) could be oftherapeutic benefit (Woodruff, T. M., et al. (2003) J Immunol 171(10):5514-5520; Jain, U., et al. (2013) Br J Pharmacol 168(2): 488-501).

There is a body of evidence suggesting a role for C5a and its receptorin pathologies of the CNS. C5aR expression is upregulated on reactiveastrocytes, microglia, and endothelial cells in an inflamed humancentral nervous system (O'Barr, S. A., et al. (2001) J Immunol 166(6):4154-4162; Gasque, P., et al. (1997) Am J Pathol 150(1): 31-41) and C5ahas been reported to be involved in the pathogenesis of manyneurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS)(Mantovani, S., et al. (2014) J Neuroimmunol 276(1-2): 213-218; Humayun,S., et al. (2009) J Neuroimmunol 210(1-2): 52-62; Woodruff, T. M., etal. (2008) J Immunol 181(12): 8727-8734), Alzheimer disease (Fonseca, M.I., et al. (2013) J Neuroinflammation 10: 25; Ager, R. R., et al. (2010)J Neurochem 113(2): 389-401), Parkinson's disease (Wang, X. J., et al.(2007) Neurochem Int 50(1): 39-50) and Huntington's disease (Singhrao etal. (1999) Experimental Neurology 159, 362-376). Furthermore C5a isfound to be elevated in the CSF of Guillain-Barre syndrome patients(Hartung, H. P., et al. (1987) Neurology 37(6): 1006-1009; Wakerley, B.R. and N. Yuki (2015) Expert Rev Neurother 15(8): 847-849) and an antiC5 antibody was found to be effective in reducing neuropathy in themouse (Halstead, S. K., et al. (2008) Brain 131 (Pt 5): 1197-1208;Basta, M. and D. R. Branch (2014) Clin Exp Immunol 178 Suppl 1: 87-88).Also, inhibition of the C5a receptor alleviates experimental CNS lupus(Zwirner, J., et al. (1999) Mol Immunol 36(13-14): 877-884; Jacob, A.,B. Hack, et al. (2010) J Neuroimmunol 221(1-2): 46-52). Therefore, C5aRantagonists provided herein may be to treat ALS, Alzheimer's disease,multiple sclerosis, Guillain-Barre syndrome, Parkinson's disease,Huntington's disease and also cognitive function decline associated withcardiopulmonary bypass surgery and related procedures in addition tocentral nervous system involvement in diseases such as SLE, Sjögren'ssyndrome and associated immunological profiles.

In many autoimmune diseases Immunoglobulin G-containing immune complex(IC) depositions are found. These contribute to the pathophysiology ofthe diseases which frequently manifest in different organs of the bodyincluding the kidneys, heart, lungs, liver, blood vessels, the nervoussystem and the skin. There are numerous such IC diseases and examplesare systemic lupus erthyematosus (SLE), cryoglobulinemia, rheumatoidarthritis, Sjögren's syndrome (Lawley, T. J., et al. (1979) J Immunol123(3): 1382-1387), Goodpasture syndrome (antiglomerular basementantibody disease), and hypersensitivity. Immune complexes are known toinduce C5 convertases leading to C5a production which subsequentlycontributes to these diseases (Karsten, C. M. and J. Kohl (2012)Immunobiology 217(11): 1067-1079). In animal models reproducing themechanisms of IC activation of complement, C5aR has been shown to playan important role. Studies show that C5aR deficient mice and the use ofa peptidic C5aR antagonist result in protection from tissue injuryinduced by ICs. (Strachan, A. J., et al. (2000) J Immunol 164(12):6560-6565; Kohl, J. and J. E. Gessner (1999) Mol Immunol 36(13-14):893-903; Baumann, U., et al. (2000) J Immunol 164(2): 1065-1070).Therefore, inhibitors of C5aR could be useful to treat IC diseasesincluding the autoimmune diseases rheumatoid arthritis (Jose, P. J., etal. (1990) Ann Rheum Dis 49(10): 747-752; Grant, E. P., et al. (2002) JExp Med 196(11): 1461-1471; Yuan, G., et al. (2003) Chin Med J (Engl)116(9): 1408-1412)), osteoarthritis, systemic lupus erythematosus(Porcel, J. M., et al. (1995) Clin Immunol Immunopathol 74(3): 283-288;Pawaria, S., et al. (2014) J Immunol 193(7): 3288-3295), lupus nephritis(Bao, L., et al. (2005) Eur J Immunol 35(8): 2496-2506), lupusglomerulonephritis and IgA nephropathy (Liu, L., et al. (2014) J ClinImmunol 34(2): 224-232), Heyman nephritis, membranous nephritis andother forms of glomerulonephritis, vasculitis, dermatomyositis(Fiebiger, E., et al. (1998) J Clin Invest 101(1): 243-251), Pemphigus,systemic sclerosis (scleroderma) (Sprott, H., et al. (2000) J Rheumatol27(2): 402-404), bronchial asthma, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome (and associatedglomerulonephritis and pulmonary hemorrhage) (Ma, R., et al. (2013) JClin Immunol 33(1): 172-178), immunovasculitis, and complement mediatedthrombotic microangiopathies including atypical haemolytic uremicsyndrome (Song, D., et al. (2015) Am J Reprod Immunol 74(4): 345-356;Davin, J. C., N. C. van de Kar (2015) Ther Adv Hematol 6(4): 171-185),mixed cryoglobulinemia, atopic dermatitis (Neuber, K., R. et al. (1991)Immunology 73(1): 83-87; Dang, L., et al. (2015) Mol Med Rep 11(6):4183-4189), and chronic urticaria (Kaplan, A. P. (2004) J Allergy ClinImmunol 114(3): 465-474; Yan, S., et al. (2014) J Dermatol Sci 76(3):240-245). Furthermore, the compound eculizumab has been shown to havepotential utility for the treatment of myasthenia gravis, andanti-phospholipid syndrome.

C5a is present in psoriatic plaques and C5aR expression has also beenreported in psoriasis where T cells, neutrophils mast cells anddendritic cells are involved in pathogenesis of the disease and arechemotactic to C5a (Diani, M., G. Altomare and E. Reali (2015) AutoimmunRev 14(4): 286-292). Neutrophil accumulation under the stratum corneumis observed in the highly inflamed areas of psoriatic plaques, andpsoriatic lesion (scale) extracts contain highly elevated levels of C5aand exhibit potent chemotactic activity towards neutrophils, an effectthat can be inhibited by addition of a C5a antibody. Furthermore, Tcells and neutrophils are chemo-attracted by C5a under certainconditions (Nataf, S., et al. (1999) J Immunol 162(7): 4018-4023; Tsuji,R. F., et al. (2000) J Immunol 165(3): 1588-1598; Werfel, T., et al.(1997) Arch Dermatol Res 289(2): 83-86; Mrowietz, U., et al. (2001) ExpDermatol 10(4): 238-245) meaning C5aR antagonists may be of benefit intreating psoriasis. Furthermore, complement has been implicated in thepathogenesis of glaucoma (Howell et al. (2011), J. Clin. Invest. 121(4):1429-1444). In addition, there is experimental evidence to suggest abeneficial role of C5aR antagonists in treating cancer with checkpointblockers. For example, an antibody against the C5aR receptor (IPH5401)has been reported to be efficacious in murine models of cancer (web pageInnate Pharma—IPH5401, 2018;https://www.innate-pharma.com/en/pipeline/iph5401-first-class-anti-c5ar-mab;Zah H., et al. (2017) Oncoimmunology 6(10): e1349587; Wang Y., et al.,(2016) Cancer Discovery 6(9) 1022-1035).

Thus, C5a and C5aR are believed to be clinically implicated invasculitic diseases or disorders, inflammatory diseases or disordersinvolving intravascular microvesicle release, immune complex (IC)diseases or disorders, neurodegenerative diseases or disorders,complement related inflammatory diseases or disorders, bullous diseasesor disorders, diseases or disorders related to ischemia and/or ischemicreperfusion injury, inflammatory bowel diseases or disorders, andautoimmune diseases or disorders; as well as in contact sensitivity oran inflammation caused by contact with artificial surfaces; increasedleukocyte and platelet activation (and infiltration to tissues thereof);pathologic sequelae associated to an intoxication or an injury such as atrauma, an hemorrhage, a shock, or surgery including transplantation,including multiple organ failure (MOF), septic shock, shock due tointoxication, or acute lung inflammatory injury; pathologic sequelaeassociated with insulin-dependent diabetes mellitus; myocardialinfarction or thrombosis; edema or an increased capillary permeability;reduction of coronary endothelial dysfunction induced by cardiopulmonarybypass and/or cardioplegia, or cancer.

There is therefore a requirement for new small organic moleculemodulators of the C5a receptor (C5aR), especially antagonists of theC5aR, that could be useful for inhibiting pathogenic events associatedwith elevated levels of C5a and/or with C5aR activation.

The present invention provides cyclic urea derivatives of formula (I)which are modulators of the C5a receptor, and, thus, may be useful forthe prevention or treatment of diseases which respond to the C5areceptor.

1) A first aspect of the invention relates to compounds of the formula(I)

wherein

-   -   Y represents NR⁵; and X and Z independently represent N or CH        (notably Y represents NR⁵; one of X and Z represents N, and the        other of X and Z represents N or CH);    -   Y represents CR⁶; one of X and Z represents NR⁷, O or S, and the        other of X and Z represents N; or    -   Y represents N; one of X and Z represents NR⁸, and the other of        X and Z represents N or CH;

ring A represents a saturated 4- to 7-membered mono-cyclic carbocyclicring containing the ring nitrogen atom to which R¹ is attached, whereinsaid ring A is optionally mono-substituted with R^(A); wherein R^(A)represents (C₁₋₄)alkyl (especially methyl) [preferably ring A issubstituted with R¹ and carries no further substituent (i.e. R^(A) isabsent)];

R¹ represents phenyl; 5-membered heteroaryl, or 6-membered heteroarylwherein said phenyl, 5-membered heteroaryl or 6-membered heteroarylindependently is mono-, di- or tri-substituted, wherein the substituentsare independently selected from (C₁₋₄)alkyl; (C₁₋₄)alkoxy;(C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy; halogen; cyano; or(C₃₋₆)cycloalkyl;

R² represents phenyl, 5-membered heteroaryl, or 6-membered heteroaryl;wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroarylindependently is mono-, or di-, or tri-substituted, wherein thesubstituents are independently selected from

-   -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy;    -   (C₁₋₃)fluoroalkyl;    -   (C₁₋₃)fluoroalkoxy;    -   halogen;    -   (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,        —O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl        optionally contains one ring oxygen atom; or    -   R^(21a)R^(21b)N—, wherein R^(21a) and R^(21b) independently        represent hydrogen or (C₁₋₄)alkyl;

R³ represents hydrogen or (C₁₋₃)alkyl (especially hydrogen);

R⁴ represents hydrogen, or (C₁₋₄)alkyl (especially hydrogen);

R⁵ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkyl which is mono-substituted with hydroxy,        (C₁₋₄)alkoxy, cyano, or R^(N1)R^(N2)N—, wherein        -   R^(N1) and R^(N2) together with the nitrogen atom form a 4-            to 6-membered saturated ring optionally containing one            further ring heteroatom selected from O and N; wherein said            ring is optionally mono-substituted with (C₁₋₄)alkyl, or            (C₁₋₄)alkoxy;        -   R^(N1) and R^(N2) are independently selected from hydrogen,            (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, or            (C₁₋₄)alkoxy-(C₂₋₄)alkylene;    -   R^(N1) represents (C₁₋₄)alkyl-C(O)—; and R^(N2) represents        hydrogen, or (C₁₋₄)alkyl; or    -   R^(N1) represents phenylsulfonyl-, wherein the phenyl is        optionally substituted by one to three substituents        independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,        cyano, or nitro; and R^(N2) represents hydrogen, or (C₁₋₄)alkyl;    -   (C₂₋₄)alkyl which is di- or tri-substituted, wherein the        substituents are independently selected from hydroxy,        (C₁₋₄)alkoxy, or R^(N1)R^(N2)N—, wherein        -   R^(N1) and R^(N2) together with the nitrogen atom form a 4-            to 6-membered saturated ring; or        -   R^(N1) and R^(N2) are independently selected from hydrogen,            or (C₁₋₄)alkyl;    -   (C₂₋₄)fluoroalkyl;    -   (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-;    -   (C₂₋₅)alkynyl;    -   (C₂₋₅)alkenyl;    -   R^(N3)R^(N4)N—C(O)—(C₀₋₄)alkylene-, wherein R^(N3) and R^(N4)        independently are hydrogen or (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy-C(O)—(C₀₋₄)alkylene-;    -   (C₁₋₄)alkoxy-C(O)—(C₂₋₄)alkylene-, wherein the (C₂₋₄)alkylene is        mono-substituted by R^(N5)R^(N6)N—, wherein R^(N5) and R^(N6)        independently are hydrogen or (C₁₋₄)alkyl    -   (C₁₋₄)alkoxy-C(O)—(C₂₋₄)alkylene-, wherein the (C₂₋₄)alkylene is        substituted by one to three halogen;    -   (C₁₋₄)alkoxy-C(O)—NH—(C₂₋₄)alkylene-, wherein the        (C₂₋₄)alkylene- is optionally substituted by one to three        halogen;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one or two substituents independently        selected from fluoro, (C₁₋₄)alkyl, nitro, or        (C₁₋₄)alkoxy-C(O)—NH—; or    -   ring^(B)-X^(B)—; wherein X^(B) is a direct bond, or        (C₁₋₄)alkylene-; and wherein ring^(B) is a 4- to 6-membered        saturated heterocyclyl containing one or two ring heteratom        independently selected from O, S, and NR^(B), wherein said        ring^(B) is attached to X^(B) at a ring carbon atom;    -   wherein said ring^(B) is optionally substituted by one or two        substituents independently selected from oxo, hydroxy, fluoro,        (C₁₋₄)alkyl or (C₁₋₄)alkoxy; and wherein    -   R^(B) independently represents        -   hydrogen;        -   (C₁₋₄)alkyl;        -   (C₂₋₄)fluoroalkyl;        -   (C₁₋₄)alkyl-C(O)—;        -   (C₁₋₄)alkoxy-C(O)—;        -   (C₁₋₄)alkyl-SO₂—;        -   R^(N7)R^(N8)N—SO₂— wherein R^(N7) and R^(N8) are            independently hydrogen or (C₁₋₄)alkyl;        -   R^(N9)R^(N10)N—C(O)— wherein R^(N9) and R^(N10) are            independently hydrogen or (C₁₋₄)alkyl;        -   Ring^(C)-O—C(O)—, and wherein ring^(C) is (C₃₋₆)cycloalkyl            optionally containing one ring oxygen atom, wherein ring^(C)            is optionally substituted with one R^(C), wherein R^(C) is            (C₁₋₄)alkyl or (C₁₋₄)fluoroalkyl; or        -   Ring^(D), wherein ring^(D) is a 5- to 6-membered heteroaryl            containing 1 to 3 heteroatoms independently selected from O,            N or S, wherein ring^(D) is unsubstituted or            mono-substituted with R^(D), wherein R^(D) is (C₁₋₄)alkyl or            (C₁₋₄)fluoroalkyl;

R⁶ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₁₋₄)fluoroalkyl; or    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one to three substituents        independently selected from halogen or (C₁₋₄)alkyl;

R⁷ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl; or    -   (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-; and

R⁸ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₂₋₄)fluoroalkyl;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one to three substituents        independently selected from halogen or (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy-C(O)—(C₁₋₄)alkylene-; or    -   (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-.

The compounds of formula (I) may contain one or more further stereogenicor asymmetric centers, such as one or more additional asymmetric carbonatoms. The compounds of formula (I) may thus be present as mixtures ofstereoisomers or preferably as pure stereoisomers. Mixtures ofstereoisomers may be separated in a manner known to a person skilled inthe art.

In case a particular compound (or generic structure) is designated as(R)- or (S)-enantiomer/as having an absolute (R)- or (S)-configuration,such designation is to be understood as referring to the respectivecompound (or generic structure) in enriched, especially essentiallypure, enantiomeric form. Likewise, in case a specific asymmetric centerin a compound is designated as being in (R)- or (S)-configuration or asbeing in a certain relative configuration, such designation is to beunderstood as referring to the compound that is in enriched, especiallyessentially pure, form with regard to the respective configuration ofsaid asymmetric center. In analogy, cis- or trans-designations (or(R*,R*) designations) are to be understood as referring to therespective stereoisomer of the respective relative configuration inenriched form, especially in essentially pure form.

The term “enriched”, when used in the context of stereoisomers, is to beunderstood in the context of the present invention to mean that therespective stereoisomer is present in a ratio of at least 70:30,especially of at least 90:10 (i.e., in a purity of at least 70% byweight, especially of at least 90% by weight), with regard to therespective other stereoisomer/the entirety of the respective otherstereoisomers.

The term “essentially pure”, when used in the context of stereoisomers,is to be understood in the context of the present invention to mean thatthe respective stereoisomer is present in a purity of at least 95% byweight, especially of at least 99% by weight, with regard to therespective other stereoisomer/the entirety of the respective otherstereoisomers.

In some instances, the compounds of formula (I) may contain tautomericforms. Such tautomeric forms are encompassed in the scope of the presentinvention. For example, in case the present compounds may containheterocyclic aromatic rings containing unsubstituted ring nitrogen atomshaving a free valency such as triazolyl, or pyrazolyl, such rings may bepresent in tautomeric forms. For example, the group pyrazol-3-ylrepresents the tautomeric forms 1H-pyrazol-3-yl and 2H-pyrazol-3-yl.Likewise, in case any of R⁵, R⁷, or R⁸ represents hydrogen, thecorresponding compounds of formula (I) may be present in form oftautomers, e.g. as is the case for the following example compounds:6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5-one;6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;4-(2-Cyclopropyl-benzyl)-6-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;4-(2-Cyclopropyl-benzyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;5-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;5-(4′-Difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;7-(2-Cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7-(2-cyclopropyl-benzyl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one.Thus, for example the compound6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-oneis a tautomeric form of6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one,both names representing the same chemical entity. Likewise, the compound5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-oneis a tautomeric form of5-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-7-(2-(trifluoromethyl)benzyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-d]pyrimidin-6-one,both names representing the same chemical entity.

The present invention also includes isotopically labelled, especially ²H(deuterium) labelled compounds of formula (I), which compounds areidentical to the compounds of formula (I) except that one or more atomshave each been replaced by an atom having the same atomic number but anatomic mass different from the atomic mass usually found in nature.Isotopically labelled, especially ²H (deuterium) labelled compounds offormula (I) and salts thereof are within the scope of the presentinvention. Substitution of hydrogen with the heavier isotope ²H(deuterium) may lead to greater metabolic stability, resulting e.g. inincreased in-vivo half-life and/or reduced dosage requirements, and/ormay lead to a modified metabolism pathway, resulting e.g. in an improvedsafety profile. In one embodiment of the invention, the compounds offormula (I) are not isotopically labelled, or they are labelled onlywith one or more deuterium atoms. In a sub-embodiment, the compounds offormula (I) are not isotopically labelled at all. Isotopically labelledcompounds of formula (I) may be prepared in analogy to the methodsdescribed hereinafter, but using the appropriate isotopic variation ofsuitable reagents or starting materials.

Deuterated groups are denominated as follows: for example the group(1,1,2,2,2-²H₅-ethyl) denominates the residue

In this patent application, a bond drawn as a dotted line shows thepoint of attachment of the radical drawn. For example, the radical drawnbelow

is a 2-fluoro-6-methyl-phenyl group.

Where the plural form is used for compounds, salts, pharmaceuticalcompositions, diseases and the like, this is intended to mean also asingle compound, salt, or the like.

Any reference to compounds of formula (I) is to be understood asreferring also to the salts (and especially the pharmaceuticallyacceptable salts) of such compounds, as appropriate and expedient.

The term “pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the subject compound and exhibitminimal undesired toxicological effects. Such salts include inorganic ororganic acid and/or base addition salts depending on the presence ofbasic and/or acidic groups in the subject compound. For reference seefor example “Handbook of Pharmaceutical Salts. Properties, Selection andUse.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008;and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere(Eds.), RSC Publishing, 2012.

Definitions provided herein are intended to apply uniformly to thecompounds of formula (I), as defined in any one of embodiments 1) to44), and, mutatis mutandis, throughout the description and the claimsunless an otherwise expressly set out definition provides a broader ornarrower definition. It is well understood that a definition orpreferred definition of a term defines and may replace the respectiveterm independently of (and in combination with) any definition orpreferred definition of any or all other terms as defined herein. If notexplicitly defined otherwise in the respective embodiment or claim,groups defined herein are unsubstituted. Wherever a saturated acyclic orcyclic group contains a heteroatom and/or is attached to a heteroatomthat is part of the rest of the molecule and/or is substituted by asubstituent that is attached through a heteroatom, such heteroatoms arepreferably distant from each other by at least two carbon atoms.

In this application, in case a certain chemical residue is defined asbeing optionally substituted with a certain number of substituents, thismeans that said residue is unsubstituted, or substituted with saidnumber of substitutents as explicitly defined.

The term “halogen” means fluorine, chlorine, bromine, or iodine,preferably fluorine or chlorine.

The term “alkyl”, used alone or in combination, refers to a saturatedstraight or branched chain hydrocarbon group containing one to fourcarbon atoms. The term “(C_(x-y))alkyl” (x and y each being an integer),refers to an alkyl group as defined before, containing x to y carbonatoms. For example a (C₁₋₄)alkyl group contains from one to four carbonatoms. Examples of (C₁₋₄)alkyl are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec.-butyl and tert.-butyl. For avoidance of any doubt,in case a group is referred to as e.g. propyl or butyl, it is meant tobe n-propyl, respectively n-butyl. Further, in case a group is referredto as (C_(0-y))alkyl group, such group is absent and any free valency ofthe point of attachment is filled with hydrogen, or it contains 1 up toy carbon atoms as set out before. Examples of (C₁₋₄)alkyl as used forsubstituents of R¹ are methyl and isopropyl, and in addition ethyl.Examples of (C₁₋₄)alkyl as used for substituents of R² are methyl andisopropyl. An example of (C₁₋₄)alkyl as used for R³ is methyl. Anexample of (C₁₋₄)alkyl as used for R⁴ is methyl. Examples of (C₁₋₄)alkylas used for R⁵ and R⁶ independently are methyl, ethyl, isopropyl,isobutyl and tert-butyl; especially methyl. An example of (C₁₋₄)alkyl asused for R⁷ and R⁸ is methyl. Examples of (C₁₋₄)alkyl as used for R^(B)are methyl, ethyl, isopropyl, and isobutyl.

The term “—(C_(x-y))alkylene-”, used alone or in combination, refers tobivalently bound alkyl group as defined before containing x to y carbonatoms. Preferably, the points of attachment of a —(C_(1-y))alkylenegroup are in 1,1-diyl, in 1,2-diyl, or in 1,3-diyl arrangement.Preferably, the points of attachment of a —(C_(2-y))alkylene group arein 1,2-diyl or in 1,3-diyl arrangement. A —(C₀)alkylene- group is absentand refers to a direct bond, thus, the term —(C₀₋₄)alkylene refers to adirect bond, or —(C₁₋₄)alkylene. An example of —(C₁₋₄)alkylene as usedfor the linker X^(B)(respectively, for the linker X^(B1) and X^(B2)) ismethylene.

Alkylene-oxy linker groups —(C₁₋₃)alkylene-O— as used for example in thesubstituents (C₃₋₆)cycloalkyl-X²¹— are to be read from left to right,i.e. they refer to the respective (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene-O—groups. An example for (C₃₋₆)cycloalkyl-X²¹— wherein X²¹ is—(C₁₋₃)alkylene-O— is cyclopropyl-methoxy. An example forR^(21a)R^(21b)N—(C₂₋₃)alkylene-O— is dimethylamino-ethoxy.

The term “alkynyl”, used alone or in combination, refers to a straightor branched hydrocarbon chain containing two to five carbon atoms andone carbon-carbon triple bond. The term “(C_(x-y))alkynyl” (x and y eachbeing an integer), refers to an alkynyl group as defined beforecontaining x to y carbon atoms. For example a (C₂₋₅)alkynyl groupcontains from two to five carbon atoms. An example of an alkynyl groupis 1,1-dimethyl-prop-2-ynyl.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O—group wherein the alkyl group is as defined before. The term“(C_(x-y))alkoxy” (x and y each being an integer) refers to an alkoxygroup as defined before containing x to y carbon atoms. For example a(C₁₋₄)alkoxy group means a group of the formula (C₁₋₄)alkyl-O— in whichthe term “(C₁₋₄)alkyl” has the previously given significance. Examplesof alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are isopropoxy,ethoxy and methoxy. An example of (C₁₋₄)alkoxy as used for substituentsof R¹ is methoxy. Examples of (C₁₋₄)alkoxy as used for substituents ofR² are methoxy, ethoxy, isopropoxy. Examples of (C₁₋₄)alkoxy as used forR⁵ being attached to (C₁₋₄)alkyl are methoxy and ethoxy.

The term “fluoroalkyl”, used alone or in combination, refers to an alkylgroup as defined before containing one to four carbon atoms in which oneor more (and possibly all) hydrogen atoms have been replaced withfluorine. The term “(C_(X). y)fluoroalkyl” (x and y each being aninteger) refers to a fluoroalkyl group as defined before containing x toy carbon atoms. For example a (C₁₋₃)fluoroalkyl group contains from oneto three carbon atoms in which one to seven hydrogen atoms have beenreplaced with fluorine. Representative examples of fluoroalkyl groupsinclude trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 2,2-difluoropropyl, 2,2-difluoro-1-methyl-ethyl,2-fluoropropyl, 2-fluoro-2-methyl-propyl. Preferred are (C₁)fluoroalkylgroups such as trifluoromethyl. Examples of (C₁₋₄)fluoroalkyl as usedfor substituents of R¹ are trifluoromethyl, and, in addition,difluoromethyl. An example of (C₁₋₄)fluoroalkyl as used for substituentsof R² is trifluoromethyl. Examples of (C₂₋₄)fluoroalkyl as used for R⁵are 2,2-difluoro-ethyl, 2,2-difluoro-propyl,2,2-difluoro-1-methyl-ethyl, 2-fluoropropyl, and2-fluoro-2-methyl-propyl. Examples of (C₂₋₄)fluoroalkyl as used for R⁷are 2-fluoro-2-methyl-propyl and 2,2-difluoro-propyl. Examples of(C₂₋₄)fluoroalkyl as used for R^(B) are 2-fluoroethyl, and2,2-difluoroethyl.

The term “fluoroalkoxy”, used alone or in combination, refers to analkoxy group as defined before containing one to three carbon atoms inwhich one or more (and possibly all) hydrogen atoms have been replacedwith fluorine. The term “(C_(x-y))fluoroalkoxy” (x and y each being aninteger) refers to a fluoroalkoxy group as defined before containing xto y carbon atoms. For example a (C₁₋₃)fluoroalkoxy group contains fromone to three carbon atoms in which one to seven hydrogen atoms have beenreplaced with fluorine. Representative examples of fluoroalkoxy groupsinclude trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy,2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are(C₁)fluoroalkoxy groups such as trifluoromethoxy. An example of(C₁₋₄)fluoroalkoxy as used for substituents of R¹ is trifluoromethoxy.An example of (C₁₋₄) fluoroalkoxy as used for substituents of R² istrifluoromethoxy.

The term “cyano” refers to a group —CN.

The term “cyano-(C₁₋₂)alkoxy” is to be read from left to right, i.e. itrefers to the respective cyano-(C₁₋₂)alkylene-O-group. An example forcyano-(C₁₋₂)alkoxy is cyano-methoxy.

The term “cycloalkyl”, used alone or in combination, refers to asaturated monocyclic hydrocarbon ring containing three to six carbonatoms. The term “(C_(x-y))cycloalkyl” (x and y each being an integer),refers to a cycloalkyl group as defined before containing x to y carbonatoms. For example a (C₃₋₆)cycloalkyl group contains from three to sixcarbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Preferred are cyclopropyl and cyclobutyl;especially cyclopropyl. An example of (C₃₋₆)cycloalkyl as used forsubstituents of R¹ is cyclopropyl. An example of (C₃₋₆)cycloalkyl asused for substituents of R² is cyclopropyl. Examples of (C₃₋₆)cycloalkylas used for R⁵ being attached to (C₀₋₄)alkylene- are cyclopropyl,cyclopentyl and cyclohexyl. An example of (C₃₋₆)cycloalkyl as used forR⁸ is cyclopropyl.

The term “(C₃₋₆)cycloalkyl-O—” as used for example in the substituents(C₃₋₆)cycloalkyl-X²¹— wherein X²¹ is —O— relates to (C₃₋₆)cycloalkyl asdefined above, attached via an —O— linker. Examples of(C₃₋₆)cycloalkyl-O— as used for substituents of R² are cyclopropyl-oxyand cyclobutyl-oxy.

The term “cycloalkyl optionally containing one ring oxygen atom”, usedalone or in combination, refers to a cycloalkyl group as defined before.In addition, one ring carbon atom of said cycloalkyl may be replaced byan oxygen atom. Examples of such groups are especially cycloalkyl groupssuch as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; as well asoxygen containing groups such as oxetanyl, tetrahydrofuranyl, andtetrahydro-2H-pyranyl. Examples of (C₃₋₆)cycloalkyl-X²¹— groups wherein“the (C₃₋₆)cycloalkyl optionally contains one ring oxygen atom” as usedfor substituents of R² are cyclopropyl, cyclopropyl-oxy, cyclobutyl-oxy,oxetan-3-yl-oxy, cyclopropyl-methoxy, tetrahydropyran-4-yl-oxy,especially oxetan-3-yl-oxy. An example of such group as used forring^(C) is oxetan-3-yl; in particular oxetan-3-yl,3-methyl-oxetan-3-yl, 3-trifluoromethyl-oxetan-3-yl.

The term “heterocyclyl”, used alone or in combination, and if notexplicitly defined in a more narrow way, refers to a saturatedmonocyclic hydrocarbon ring containing one to three (especially one)ring heteroatoms independently selected from nitrogen, sulfur, andoxygen. The term “(C_(x-y))heterocyclyl” refers to such a heterocyclylgroup containing x to y ring atoms. Heterocyclyl groups areunsubstituted or substituted as explicitly defined; wherein in case aring nitrogen atom having a free valency is present, such ring nitrogenatom may be substituted as explicitly defined, in addition to further(optional) substituents of such heterocycle. Oxo substituents, ifpresent, are especially attached to a ring carbon atom in alpha positionto a ring nitrogen (thus forming together with the nitrogen an amidegroup, or, in case a ring oxygen is additionally adjacent, a carbamategroup, or, in case second ring nitrogen is additionally adjacent, a ureagroup); or two oxo substituents are substituents of a ring sulfur ringatom (thus forming an —SO₂— group).

Heterocyclyl groups as used for the group ring^(B) are attached to restof the molecule (i.e. to X^(B)) at a ring carbon atom, comprise onesubstituted ring nitrogen atom NR^(B) wherein R^(B) is as explicitlydefined, and are, in addition to R^(B), optionally substituted asexplicitly defined. Examples of heterocyclyl groups as used for thegroup ring^(B) are oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl,azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl; in particularoxetan-3-yl, azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, and piperidin-4-yl.

Examples of groups R^(N1)R^(N2)N— wherein R^(N1) and R^(N2) togetherwith the nitrogen atom form a 4- to 6-membered saturated ring optionallycontaining one further ring heteroatom selected from O and N areazetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, andmorpholin-4-yl; in particular 3-methoxy-azetidin-1-yl, pyrrolidin-1-yl,piperidin-1-yl, 4-methyl-piperazin-1-yl, and morpholin-4-yl.

Examples of ring A representing “a saturated 4- to 7-memberedmono-cyclic carbocyclic ring containing the ring nitrogen atom to whichR¹ is attached” are azetidin-1,3-diyl, pyrrolidin-1,3-diyl,piperidin-1,4-diyl, piperidin-1,3-yl, and azepan-1,4-diyl; as well asthe substituted groups 3-methyl-pyrrolidin-1,3-diyl, and4-methyl-piperidin-1,4-diyl.

The substituent phenyl as used for R¹ independently is mono-, di- ortri-substituted, notably mono-, or di-substituted, especially mono- ordi-substituted wherein at least one substituent is attached in orthoposition with regard to the point of attachment of the rest of themolecule. Examples are mono-substituted phenyl groups such as2-methoxy-phenyl; and di-substituted phenyl groups such as2-chloro-6-methyl-phenyl, 2-fluoro-6-methyl-phenyl, 2,6-dimethyl-phenyl,2-methoxy-6-methyl-phenyl, 2-fluoro-6-cyano-phenyl,2-fluoro-6-trifluoromethyl-phenyl, 2-fluoro-6-trifluoromethoxy-phenyl,and, in addition, 2,6-difluorophenyl, 2-chloro-6-fluoro-phenyl,2-bromo-6-fluoro-phenyl, 2-fluoro-6-ethyl-phenyl,2-fluoro-6-difluoromethyl-phenyl, and 2-fluoro-6-cyclopropyl-phenyl.

The substituent phenyl as used for R² is mono-, di- or tri-substituted,notably mono-, or di-substituted, especially mono- or di-substitutedwherein at least one substituent is attached in ortho position withregard to the point of attachment of the rest of the molecule. Examplesare mono-substituted phenyl group such as 2-chloro-phenyl,2-cyclopropyl-phenyl, 2-isopropyl-phenyl, 2-ethoxy-phenyl,2-trifluoromethyl-phenyl, 2-isopropoxy-phenyl, 2-cyclopropoxy-phenyl,2-(oxetan-3-yloxy)-phenyl, 2-cyclopropylmethoxy-phenyl,2-trifluoromethoxy-phenyl; di-substituted phenyl groups such as2-fluoro-6-trifluoromethyl-phenyl and 2-bromo-6-trifluoromethyl-phenyl;and tri-substituted phenyl groups such as2,4-difluoro-6-isopropoxy-phenyl.

The term “heteroaryl”, used alone or in combination, means a 5- to6-membered monocyclic aromatic ring containing one to a maximum of threeheteroatoms, each independently selected from oxygen, nitrogen andsulfur. Examples of such heteroaryl groups are 5-membered heteroarylsuch as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl,thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl; and 6-membered heteroaryl such as pyridinyl, pyrimidinyl,pyridazinyl, and pyrazinyl. The above-mentioned heteroaryl groups areunsubstituted or substituted as explicitly defined. In case 5- or6-membered heteroaryl group is substituted in ortho-position with regardto the point of attachment of the rest of the molecule, it is understoodthat such substituent is attached in direct neighbourhood with regard tothe point of attachment of the rest of the molecule, i.e. in a relative1,2-arrangement. Examples of heteroaryl as used for the substituent R¹are notably 6-membered heteroaryl containing one or two nitrogen atoms,or 5-membered heteroaryl containing one or two ring nitrogen atoms andoptionally one further heteroatom selected from nitrogen, oxygen orsulfur; in particular 4-chloro-2,5-dimethyl-2H-pyrazol-3-yl,2,5-dimethyl-4-cyano-pyrazol-3-yl, 3-fluoro-pyridin-2-yl,3-methoxy-pyridin-2-yl, 2-methoxy-4-methyl-pyridin-3-yl,2-fluoro-4-methyl-pyridin-3-yl, 2-methyl-4-fluoro-pyridin-3-yl,2-cyano-4-methyl-pyridin-3-yl, 2,4-dimethoxy-pyridin-3-yl,4-methoxy-6-methyl-pyrimidin-5-yl, 4,6-dimethoxy-pyrimidin-5-yl, and, inaddition, 2-methoxy-4-chloro-pyridin-3-yl,2-methoxy-4-difluoromethyl-pyridin-3-yl, and2-methoxy-4-trifluoromethyl-pyridin-3-yl. Examples of heteroaryl as usedfor the substituent R² are especially 6-membered heteroaryl containingone or two nitrogen atoms; or 5-membered heteroaryl containing one ortwo ring nitrogen atoms and one further heteroatom independentlyselected from nitrogen, oxygen or sulfur; in particular4-isopropyl-pyrimidin-5-yl, 3-trifluoromethyl-pyrazin-2-yl,3-trifluoromethyl-pyridin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,6-deutero-3-trifluoromethyl-pyridin-2-yl,6-chloro-3-trifluoromethyl-pyridin-2-yl,6-fluoro-3-trifluoromethyl-pyridin-2-yl,6-methylamino-3-trifluoromethyl-pyridin-2-yl,6-methoxy-3-trifluoromethyl-pyridin-2-yl,6-dimethylamino-3-trifluoromethyl-pyridin-2-yl,4-trifluoromethyl-pyridin-3-yl, and 4-trifluoromethyl-thiazol-5-yl.Examples of heteroaryl as used for the substituent ring^(D) are notably5-membered heteroaryl containing one or two nitrogen atoms andoptionally one further heteroatom independently selected from nitrogen,oxygen or sulfur, such as especially oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, thiadiazolyl; in particular 5-methyl-[1,3,4]-oxadiazol-2-yl,5-isopropyl-[1,3,4]-oxadiazol-2-yl and5-trifluoromethyl-[1,3,4]-oxadiazol-2-yl.

Further embodiments of the invention are presented hereinafter: 2) Asecond embodiment relates to compounds according to embodiment 1),wherein ring A represents a fragment

wherein said ring A is selected from azetidin-1,3-diyl,pyrrolidin-1,3-diyl, piperidin-1,4-diyl, piperidin-1,3-yl, andazepan-1,4-diyl (notably ring A is pyrrolidin-1,3-diyl,piperidin-1,4-diyl or azepan-1,4-diyl; especially piperidin-1,4-diyl);and wherein said ring A is substituted with R¹ on the ring nitrogen atom(i.e. in respective position 1), and optionally substituted on the ringcarbon atom linked to the rest of the molecule (i.e. in position 3 ofazetidin-1,3-diyl, pyrrolidin-1,3-diyl and piperidin-1,3-yl,respectively, in position 4 of piperidin-1,4-diyl and azepan-1,4-diyl)with R^(A), wherein R^(A) is (C₁₋₄)alkyl (especially methyl).

In a sub-embodiment, ring A (wherein especially ring A ispiperidin-1,4-diyl) is substituted with R¹ and carries no furthersubstituent (i.e. R^(A) in the fragment above is absent and the freevalency of the respective ring carbon atom is saturated with hydrogen)].

3) Another embodiment relates to compounds according to embodiments 1)or 2), wherein ring A is substituted with R¹ and carries no furthersubstituent

[i.e. ring A represents a fragment:

4) Another embodiment relates to compounds according to any one ofembodiments 1) to 3), wherein Y represents NR⁵; one of X and Zrepresents N, and the other of X and Z represents N or CH.

In particular, this embodiment encompasses ring groups wherein

-   -   Y represents NR⁵, X represents N and Z represents CH;    -   Y represents NR⁵, X represents CH and Z represents N; or    -   Y represents NR⁵, X represents N and Z represents N.

5) Another embodiment relates to compounds according to any one ofembodiments 1) to 3), wherein

-   -   Y represents NR⁵, X represents N and Z represents CH.

6) Another embodiment relates to compounds according to any one ofembodiments 1) to 3), wherein

-   -   Y represents CR⁶; one of X and Z represents NR⁷, O or S, and the        other of X and Z represents N.

In particular, this embodiment encompasses ring groups wherein

-   -   Y represents CR⁶; X represents O and Z represents N;    -   Y represents CR⁶; X represents S and Z represents N; or    -   Y represents CR⁶; X represents NR⁷ and Z represents N; or    -   Y represents CR⁶; X represents N and Z represents NR⁷.

7) Another embodiment relates to compounds according to any one ofembodiments 1) to 3), wherein

-   -   Y represents CH; X represents NR⁷ and Z represents N;    -   Y represents CH; X represents N and Z represents NR⁷;    -   Y represents N; X represents NR⁸ and Z represents CH;    -   Y represents N; X represents CH and Z represents NR⁸;    -   Y represents N; X represents NR⁸ and Z represents N; or    -   Y represents N; X represents N and Z represents NR⁸.

8) Another embodiment relates to compounds according to any one ofembodiments 1) to 3), wherein

-   -   Y represents CH; X represents N, and Z represents NR⁷;    -   Y represents N; X represents CH, and Z represents NR⁸; or    -   Y represents N; X represents N and Z represents NR⁸.

9) Another embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein R¹ represents

-   -   phenyl which is mono-, di- or tri-substituted (notably mono-, or        di-substituted, especially mono- or di-substituted wherein at        least one substituent is attached in ortho position with regard        to the point of attachment of the rest of the molecule), wherein        the substituents are independently selected from (C₁₋₄)alkyl        (especially methyl, isopropyl); (C₁₋₄)alkoxy (especially        methoxy); (C₁₋₃)fluoroalkyl (especially trifluoromethyl, or        difluoromethyl); (C₁₋₃)fluoroalkoxy (especially        trifluoromethoxy); halogen (especially fluoro or chloro); cyano;        and (C₃₋₆)cycloalkyl (especially cyclopropyl);    -   5-membered heteroaryl containing one or two ring nitrogen atoms        and optionally one further heteroatom selected from nitrogen,        oxygen or sulfur (notably pyrazolyl; especially 2H-pyrazol-3-yl)        which is mono-, or di- or tri-substituted (notably di- or        tri-substituted), wherein the substituents are independently        selected from (C₁₋₄)alkyl (especially methyl); halogen        (especially chloro); cyano; and (C₃₋₆)cycloalkyl (especially        cyclopropyl); or    -   6-membered heteroaryl containing one or two nitrogen atoms        (notably pyridinyl, pyrimidinyl; especially pyridine-2-yl,        pyridine-3-yl, pyrimidin-5-yl) which is mono-, or di-substituted        (wherein notably at least one substituent is attached in ortho        position with regard to the point of attachment of the rest of        the molecule; especially such 6-membered heteroaryl is        di-substituted in both ortho positions), wherein the        substituents are independently selected from (C₁₋₄)alkyl        (especially methyl, isopropyl); (C₁₋₄)alkoxy (especially        methoxy); halogen (especially fluoro); cyano; (C₃₋₆)cycloalkyl        (especially cyclopropyl), and, in addition, (C₃)fluoroalkyl        (especially trifluoromethyl, difluoromethyl).

10) Another embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein R¹ represents

-   -   phenyl which is mono-, di- or tri-substituted (notably mono-, or        di-substituted, especially mono- or di-substituted wherein at        least one substituent is attached in ortho position with regard        to the point of attachment of the rest of the molecule), wherein        the substituents are independently selected from (C₁₋₄)alkyl        (especially methyl, isopropyl); (C₁₋₄)alkoxy (especially        methoxy); (C₁₋₃)fluoroalkyl (especially trifluoromethyl, or        difluoromethyl); (C₁₋₃)fluoroalkoxy (especially        trifluoromethoxy); halogen (especially fluoro or chloro); cyano;        and (C₃₋₆)cycloalkyl (especially cyclopropyl);    -   pyrazolyl (especially 2H-pyrazol-3-yl) which is mono-, or di- or        tri-substituted (notably tri-substituted), wherein the        substituents are independently selected from (C₁₋₄)alkyl        (especially methyl); halogen (especially chloro); cyano; and        (C₃₋₆)cycloalkyl (especially cyclopropyl); or    -   pyridinyl, in particular pyridine-2-yl and pyridine-3-yl        (especially pyridine-3-yl) which is mono-, or di-substituted        (wherein notably at least one substituent is attached in ortho        position with regard to the point of attachment of the rest of        the molecule; especially such pyridinyl is di-substituted in        both ortho positions), wherein the substituents are        independently selected from (C₁₋₄)alkyl (especially methyl,        isopropyl); (C₁₋₄)alkoxy (especially methoxy); halogen        (especially fluoro); cyano; (C₃₋₆)cycloalkyl (especially        cyclopropyl); and, in addition, (C₁₋₃)fluoroalkyl (especially        trifluoromethyl, difluoromethyl);    -   pyrimidinyl, in particular pyrimidin-5-yl, wherein which is        mono-, or di-substituted (wherein notably at least one        substituent is attached in ortho position with regard to the        point of attachment of the rest of the molecule; especially such        pyrimidinyl is di-substituted in both ortho positions), wherein        the substituents are independently selected from (C₁₋₄)alkyl        (especially methyl, isopropyl); and (C₁₋₄)alkoxy (especially        methoxy).

11) Another embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein R¹ represents

-   -   phenyl which is mono-, di- or tri-substituted (notably mono-, or        di-substituted, especially mono- or di-substituted wherein at        least one substituent is attached in ortho position with regard        to the point of attachment of the rest of the molecule), wherein        the substituents are independently selected from (C₁₋₄)alkyl        (especially methyl, isopropyl); (C₁₋₄)alkoxy (especially        methoxy); (C₁₋₃)fluoroalkyl (especially trifluoromethyl, or        difluoromethyl); (C₁₋₃)fluoroalkoxy (especially        trifluoromethoxy); halogen (especially fluoro and chloro); and        cyano;    -   pyrazolyl (especially 2H-pyrazol-3-yl) which is mono-, or di- or        tri-substituted (notably tri-substituted), wherein the        substituents are independently selected from (C₁₋₄)alkyl        (especially methyl); and halogen (especially chloro);    -   pyridinyl, in particular pyridine-2-yl and pyridine-3-yl        (especially pyridine-3-yl) which is mono-, or di-substituted        (wherein notably at least one substituent is attached in ortho        position with regard to the point of attachment of the rest of        the molecule; especially such pyridinyl is di-substituted in        both ortho positions), wherein the substituents are        independently selected from (C₁₋₄)alkyl (especially methyl,        isopropyl); (C₁₋₄)alkoxy (especially methoxy); halogen        (especially fluoro); and, in addition, (C₁₋₃)fluoroalkyl        (especially trifluoromethyl, difluoromethyl).

12) Another embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein R¹ represents

-   -   phenyl which is mono-, di- or tri-substituted (notably mono-, or        di-substituted, especially mono- or di-substituted wherein at        least one substituent is attached in ortho position with regard        to the point of attachment of the rest of the molecule), wherein        the substituents are independently selected from (C₁₋₄)alkyl        (especially methyl); (C₁₋₄)alkoxy (especially methoxy);        (C₁₋₃)fluoroalkyl (especially trifluoromethyl, or        difluoromethyl); (C₁₋₃)fluoroalkoxy (especially        trifluoromethoxy); halogen (especially fluoro and chloro);        cyano; and, in addition, cyclopropyl;    -   pyridinyl (notably pyridine-2-yl or pyridine-3-yl; especially        pyridine-3-yl) which is mono-, or di-substituted (wherein        notably at least one substituent is attached in ortho position        with regard to the point of attachment of the rest of the        molecule; especially such pyridinyl is di-substituted in both        ortho positions), wherein the substituents are independently        selected from (C₁₋₄)alkyl (especially methyl); (C₁₋₄)alkoxy        (especially methoxy); halogen (especially fluoro); and, in        addition, (C₁₋₃)fluoroalkyl (especially trifluoromethyl,        difluoromethyl) and cyclopropyl.

13) Another embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein R¹ represents

-   -   phenyl which is mono- or di-substituted, wherein at least one        substituent is attached in ortho position with regard to the        point of attachment of the rest of the molecule (especially        di-substituted in both ortho positions), wherein the        substituents are independently selected from (C₁₋₄)alkyl        (especially methyl, isopropyl); (C₁₋₄)alkoxy (especially        methoxy); halogen (especially fluoro or chloro); cyano; and, in        addition, (C₁₋₃)fluoroalkyl (especially trifluoromethyl,        difluoromethyl) and cyclopropyl; or    -   pyridinyl which is di-substituted, wherein at least one        substituent is attached in ortho position with regard to the        point of attachment of the rest of the molecule (especially        di-substituted in both ortho positions), wherein the        substituents are independently selected from (C₁₋₄)alkyl        (especially methyl, isopropyl); (C₁₋₄)alkoxy (especially        methoxy); halogen (especially fluoro); and, in addition,        (C₁₋₃)fluoroalkyl (especially trifluoromethyl, difluoromethyl).

14) Another embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein R¹ represents phenyl which is mono-, ordi-substituted; wherein at least one substituent is attached in orthoposition with regard to the point of attachment of the rest of themolecule;

-   -   wherein said ortho-substituent is (C₁₋₄)alkyl (especially        methyl); (C₁₋₄)alkoxy (especially methoxy); halogen (especially        fluoro); or (C₁₋₃)fluoroalkyl (especially difluoromethyl);        [especially such substituent is methyl, methoxy, fluoro, or        difluoromethyl; in particular methyl, fluoro, or        difluoromethyl];    -   and, if present, the remaining substituent independently is        methyl; methoxy; halogen; or cyano; [especially such remaining        substituent is methyl, methoxy or fluoro; in particular methyl        or fluoro];    -   wherein especially such remaining substituent is attached in the        other ortho position with regard to the point of attachment of        the rest of the molecule.

15) Another embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein R¹ is 2-chloro-6-methyl-phenyl,2-fluoro-6-methyl-phenyl, 2,6-dimethyl-phenyl,2-methoxy-6-methyl-phenyl, 2-fluoro-6-cyano-phenyl,2-fluoro-6-trifluoromethyl-phenyl, 2-fluoro-6-trifluoromethoxy-phenyl,4-chloro-2,5-dimethyl-2H-pyrazol-3-yl,2,5-dimethyl-4-cyano-pyrazol-3-yl, 3-fluoro-pyridin-2-yl,3-methoxy-pyridin-2-yl, 2-methoxy-4-methyl-pyridin-3-yl,2-fluoro-4-methyl-pyridin-3-yl, 2-methyl-4-fluoro-,2-cyano-4-methyl-pyridin-3-yl, 2,4-dimethoxy-pyridin-3-yl,4-methoxy-6-methyl-pyrimidin-5-yl, or 4,6-dimethoxy-pyrimidin-5-yl, and,in addition, 2,6-difluorophenyl, 2-chloro-6-fluoro-phenyl,2-bromo-6-fluoro-phenyl, 2-fluoro-6-difluoromethyl-phenyl,2-fluoro-6-cyclopropyl-phenyl, 2-methoxy-4-chloro-pyridin-3-yl,2-methoxy-4-difluoromethyl-pyridin-3-yl, or2-methoxy-4-trifluoromethyl-pyridin-3-yl [especially R¹ is2-chloro-6-methyl-phenyl, 2-fluoro-6-methyl-phenyl, 2,6-dimethyl-phenyl,2-methoxy-6-methyl-phenyl, 2-fluoro-6-cyano-phenyl,2-fluoro-6-trifluoromethyl-phenyl, 2-fluoro-6-trifluoromethoxy-phenyl,2-methoxy-4-methyl-pyridin-3-yl, or 2-cyano-4-methyl-pyridin-3-yl; or R¹is 2,6-difluorophenyl, 2-chloro-6-fluoro-phenyl,2-bromo-6-fluoro-phenyl, 2-fluoro-6-difluoromethyl-phenyl,2-fluoro-6-cyclopropyl-phenyl, 2-methoxy-4-chloro-pyridin-3-yl,2-methoxy-4-difluoromethyl-pyridin-3-yl, or2-methoxy-4-trifluoromethyl-pyridin-3-yl].

16) Another embodiment relates to compounds according to any one ofembodiments 1) to 15), wherein R² represents phenyl, 5-memberedheteroaryl (notably 5-membered heteroaryl containing one or two ringnitrogen atoms and one further heteroatom independently selected fromnitrogen, oxygen or sulfur; especially thiazolyl); or 6-memberedheteroaryl (notably 6-membered heteroaryl containing one or two nitrogenatoms; especially pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl);wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl,independently is mono-, or di-, or tri-substituted (notably mono-, ordi-substituted, especially mono-, or di-substituted wherein at least onesubstituent is attached in ortho position with regard to the point ofattachment of the rest of the molecule), wherein the substituents areindependently selected from

-   -   (C₁₋₄)alkyl (especially methyl, isopropyl);    -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, isopropoxy);    -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);    -   (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy);    -   halogen (especially bromo, chloro, fluoro);    -   (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,        —O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl        contains one optional ring oxygen atom; [especially such group        (C₃₋₆)cycloalkyl-X²¹— is cyclopropyl, cyclopropyl-oxy,        oxetan-3-yl-oxy, cyclopropyl-methoxy]; and    -   R^(21a)R^(21b)N—, wherein R^(21a) and R^(21b) independently        represent hydrogen or (C₁₋₄)alkyl; [especially such group        R^(21a)R^(21b)N— is dimethylamino, methylamino];

wherein preferably said substituent in ortho position, if present, is(C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, or(C₃₋₆)cycloalkyl-X²¹— (especially such ortho substituent istrifluoromethyl); and the other substituents, if present, areindependently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, andR^(21a)R^(21b)N—.

17) Another embodiment relates to compounds according to any one ofembodiments 1) to 15), wherein R² represents

-   -   phenyl; wherein said phenyl is mono-, or di-, or tri-substituted        (notably mono-, or di-substituted, especially mono-, or        di-substituted wherein at least one substituent is attached in        ortho position with regard to the point of attachment of the        rest of the molecule), wherein the substituents are        independently selected from        -   (C₁₋₄)alkyl (especially methyl, isopropyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, isopropoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy);        -   halogen (especially bromo, chloro, fluoro); and        -   (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,            —O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl            contains one optional ring oxygen atom; [especially such            group (C₃₋₆)cycloalkyl-X²¹— is cyclopropyl, cyclopropyl-oxy,            oxetan-3-yl-oxy, cyclopropyl-methoxy];    -   wherein preferably said substituent in ortho position, if        present, is (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,        (C₁₋₃)fluoroalkoxy, or (C₃₋₆)cycloalkyl-X²¹— (especially such        ortho substituent is trifluoromethyl); and the other        substituents, if present, are independently selected from        (C₁₋₄)alkyl, (C₁₋₄)alkoxy, and halogen; or    -   5-membered heteroaryl containing one or two ring nitrogen atoms        and one further heteroatom independently selected from nitrogen,        oxygen or sulfur (notably thiazolyl; especially thiazol-5-yl);        wherein said 5-membered heteroaryl is mono-, or di-substituted        (especially di-substituted), wherein the substituents are        independently selected from        -   (C₁₋₄)alkyl (especially methyl, isopropyl);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl); and        -   (C₃₋₆)cycloalkyl (especially cyclopropyl); or    -   6-membered heteroaryl containing one or two nitrogen atoms        (notably pyridinyl, pyrimidinyl, or pyrazinyl; especially        pyridin-2-yl, pyridin-3-yl, pyramid-5-yl or pyrazin-2-yl);        wherein said 6-membered heteroaryl independently is mono-, or        di-substituted (notably mono-, or di-substituted, especially        mono-, or di-substituted wherein at least one substituent is        attached in ortho position with regard to the point of        attachment of the rest of the molecule), wherein the        substituents are independently selected from        -   (C₁₋₄)alkyl (especially methyl, isopropyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, isopropoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   halogen (especially chloro, fluoro); and        -   (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,            —O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl            contains one optional ring oxygen atom; [especially such            group (C₃₋₆)cycloalkyl-X²¹— is cyclopropoxy,            oxetan-3-yl-oxy, cyclopropyl-methoxy];        -   R^(21a)R^(21b)N—, wherein R^(21a) and R^(21b) independently            represent hydrogen or (C₁₋₄)alkyl; [especially such group            R^(21a)R^(21b)N— is dimethylamino, methylamino];    -   wherein preferably said substituent in ortho position, if        present, is (C₁₋₃)fluoroalkyl (especially trifluoromethyl), and        the other substituents, if present, are selected from        (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, and R^(21a)R^(21b)N—.

18) Another embodiment relates to compounds according to any one ofembodiments 1) to 15), wherein R² represents

-   -   phenyl; wherein said phenyl is mono-, or di-substituted (notably        mono-substituted, especially mono-substituted in ortho position        with regard to the point of attachment of the rest of the        molecule), wherein the substituents are independently selected        from        -   (C₁₋₄)alkyl (especially isopropyl);        -   (C₁₋₄)alkoxy (especially, ethoxy, isopropoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy);        -   halogen (especially chloro, fluoro); and        -   (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,            —O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl            contains one optional ring oxygen atom; [especially such            group (C₃₋₆)cycloalkyl-X²¹— is cyclopropoxy,            oxetan-3-yl-oxy, cyclopropyl-methoxy];    -   wherein preferably said substituent in ortho position, if        present, is (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₁₋₃)fluoroalkyl,        (C₁₋₃)fluoroalkoxy, or (C₃₋₆)cycloalkyl-X²¹— (especially such        ortho substituent is trifluoromethyl); or    -   6-membered heteroaryl containing one or two nitrogen atoms        (notably pyridinyl; especially pyridin-2-yl); wherein said        6-membered heteroaryl independently is mono-, or di-substituted        (notably mono-, or di-substituted, especially mono-, or        di-substituted wherein at least one substituent is attached in        ortho position with regard to the point of attachment of the        rest of the molecule), wherein the substituents are        independently selected from        -   (C₁₋₄)alkoxy (especially methoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   halogen (especially chloro, fluoro); and        -   (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,            —O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl            contains one optional ring oxygen atom; [especially such            group (C₃₋₆)cycloalkyl-X²¹— is cyclopropoxy,            oxetan-3-yl-oxy, cyclopropyl-methoxy];    -   wherein preferably said substituent in ortho position, if        present, is (C₁₋₃)fluoroalkyl (especially trifluoromethyl); and        the other substituent, if present, is selected from (C₁₋₄)alkyl,        (C₁₋₄)alkoxy, and halogen.

19) Another embodiment relates to compounds according to any one ofembodiments 1) to 15), wherein R² is 2-chloro-phenyl,2-cyclopropyl-phenyl, 2-isopropyl-phenyl, 2-ethoxy-phenyl,2-trifluoromethyl-phenyl, 2-isopropoxy-phenyl, 2-cyclopropoxy-phenyl,2-(oxetan-3-yloxy)-phenyl, 2-cyclopropylmethoxy-phenyl,2-fluoro-6-trifluoromethyl-phenyl, 2-bromo-6-trifluoromethyl-phenyl,2-trifluoromethoxy-phenyl, 2,4-difluoro-6-isopropoxy-phenyl,4-isopropyl-pyramid-5-yl, 3-trifluoromethyl-pyrazin-2-yl,3-trifluoromethyl-pyridin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,6-chloro-3-trifluoromethyl-pyridin-2-yl,6-fluoro-3-trifluoromethyl-pyridin-2-yl,6-methylamino-3-trifluoromethyl-pyridin-2-yl,6-methoxy-3-trifluoromethyl-pyridin-2-yl,6-dimethylamino-3-trifluoromethyl-pyridin-2-yl,4-trifluoromethyl-pyridin-3-yl or2-methyl-4-trifluoromethyl-thiazol-5-yl [especially 2-chloro-phenyl,2-cyclopropyl-phenyl, 2-isopropyl-phenyl, 2-ethoxy-phenyl,2-trifluoromethyl-phenyl, 2-isopropoxy-phenyl, 2-cyclopropoxy-phenyl,2-(oxetan-3-yloxy)-phenyl, 2-cyclopropylmethoxy-phenyl,2-fluoro-6-trifluoromethyl-phenyl, 2-trifluoromethoxy-phenyl,3-trifluoromethyl-pyridin-2-yl, 6-chloro-3-trifluoromethyl-pyridin-2-yl,6-fluoro-3-trifluoromethyl-pyridin-2-yl, or6-methoxy-3-trifluoromethyl-pyridin-2-yl; in particular2-trifluoromethyl-phenyl, 3-trifluoromethyl-pyridin-2-yl,6-chloro-3-trifluoromethyl-pyridin-2-yl,6-fluoro-3-trifluoromethyl-pyridin-2-yl].

20) Another embodiment relates to compounds according to any one ofembodiments 1) to 19), wherein R³ represents hydrogen, or methyl(especially hydrogen).

21) Another embodiment relates to compounds according to any one ofembodiments 1) to 20), wherein R⁴ represents hydrogen or methyl(especially hydrogen).

22) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl (especially methyl);    -   (C₁₋₄)alkyl which is mono-substituted with (C₁₋₄)alkoxy        (especially methoxy, ethoxy), or cyano;    -   (C₂₋₄)alkyl which is mono-substituted with hydroxy or        R^(N1)R^(N2)N—, wherein        -   R^(N1) and R^(N2) together with the nitrogen atom form a 4-            to 6-membered saturated ring optionally containing one            further ring heteroatom selected from O and N; wherein said            ring is optionally mono-substituted with (C₁₋₄)alkyl, or            (C₁₋₄)alkoxy;        -   R^(N1) and R^(N2) are independently selected from hydrogen,            (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, or            (C₁₋₄)alkoxy-(C₂₋₄)alkylene;        -   R^(N1) represents (C₁₋₄)alkyl-C(O)—; and R^(N2) represents            hydrogen, or (C₁₋₄)alkyl; or        -   R^(N1) represents phenylsulfonyl-, wherein the phenyl is            optionally substituted by one to three substituents            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, cyano, or nitro; and R^(N2) represents hydrogen, or            (C₁₋₄)alkyl;    -   (C₃₋₄)alkyl which is di-substituted, wherein the substituents        are independently selected from hydroxy, (C₁₋₄)alkoxy, or        R^(N11)R^(N12)N—, wherein R^(N11) and R^(N12) are independently        selected from hydrogen, or (C₁₋₄)alkyl;    -   (C₂₋₄)fluoroalkyl;    -   (C₂₋₅)alkynyl;    -   (C₂₋₅)alkenyl;    -   R^(N3)R^(N4)N—C(O)—(C₁₋₄)alkylene-, wherein R^(N3) and R^(N4)        independently are hydrogen or (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy-C(O)—(C₁₋₄)alkylene-;    -   (C₁₋₄)alkoxy-C(O)—(C₂₋₄)alkylene-, wherein the (C₂₋₄)alkylene is        mono-substituted by R^(N5)R^(N6)N—, wherein R^(N5) and R^(N6)        independently are hydrogen or (C₁₋₄)alkyl    -   (C₁₋₄)alkoxy-C(O)—(C₂₋₄)alkylene-, wherein the (C₂₋₄)alkylene is        substituted by one to three halogen;    -   (C₁₋₄)alkoxy-C(O)—NH—(C₂₋₄)alkylene-, wherein the        (C₂₋₄)alkylene- is optionally substituted by one to three        halogen;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one or two substituents independently        selected from fluoro, methyl, nitro, or (C₁₋₄)alkoxy-C(O)—NH—;        or    -   ring^(B)-X^(B)—; wherein X^(B) is a direct bond, or        (C₁₋₄)alkylene- (especially methylene); and wherein ring^(B) is        a 4- to 6-membered saturated heterocyclyl containing one ring        heteratom which is 0, or NR^(B), wherein said ring^(B) is        attached to X^(B) at a ring carbon atom;    -   wherein said ring^(B) is optionally substituted by one or two        substituents independently selected from oxo, hydroxy, fluoro,        (C₁₋₄)alkyl (especially methyl) or (C₁₋₄)alkoxy (especially        methoxy); and wherein R^(B) independently represents        -   hydrogen;        -   (C₁₋₄)alkyl;        -   (C₂₋₄)fluoroalkyl;        -   (C₁₋₄)alkyl-C(O)—;        -   (C₁₋₄)alkoxy-C(O)—;        -   (C₁₋₄)alkyl-SO₂—;        -   R^(N7)R^(N8)N—SO₂— wherein R^(N7) and R^(N8) are            independently hydrogen or (C₁₋₄)alkyl;        -   R^(N9)R^(N10)N—C(O)— wherein R^(N9) and R^(N10) are            independently hydrogen or (C₁₋₄)alkyl;        -   Ring^(C)-O—C(O)—, and wherein ring^(C) is (C₃₋₆)cycloalkyl            optionally containing one ring oxygen atom, wherein ring^(C)            is optionally substituted with one R^(C), wherein R^(C) is            (C₁₋₄)alkyl or (C₁₋₄)fluoroalkyl; or        -   Ring^(D), wherein ring^(D) is a 5- to 6-membered heteroaryl            containing 1 to 3 heteroatoms independently selected from O,            N or S (especially 5-membered heteroaryl containing one or            two nitrogen atoms and optionally one further heteroatom            independently selected from nitrogen, oxygen or sulfur),            wherein ring^(D) is unsubstituted or mono-substituted with            R^(D), wherein R^(D) is (C₁₋₄)alkyl or (C₁₋₄)fluoroalkyl.

23) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkyl which is mono-substituted with (C₁₋₄)alkoxy        (especially methoxy, ethoxy), or cyano;    -   (C₂₋₄)alkyl which is mono-substituted with hydroxy or        R^(N1)R^(N2)N—, wherein        -   R^(N1) and R^(N2) together with the nitrogen atom form a 4-            to 6-membered saturated ring optionally containing one            further ring heteroatom selected from O and N; wherein said            ring is optionally mono-substituted with (C₁₋₄)alkyl, or            (C₁₋₄)alkoxy;        -   R^(N1) and R^(N2) are independently selected from hydrogen,            (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, or            (C₁₋₄)alkoxy-(C₂₋₄)alkylene;        -   R^(N1) represents (C₁₋₄)alkyl-C(O)—; and R^(N2) represents            hydrogen, or (C₁₋₄)alkyl; or        -   R^(N1) represents phenylsulfonyl-, wherein the phenyl is            optionally substituted by one to three substituents            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, cyano, or nitro; and R^(N2) represents hydrogen, or            (C₁₋₄)alkyl;    -   (C₃₋₄)alkyl which is di-substituted, wherein the substituents        are independently selected from hydroxy, (C₁₋₄)alkoxy, or        R^(N11)R^(N12)N—, wherein R^(N11) and R^(N12) are independently        selected from hydrogen, or (C₁₋₄)alkyl;    -   (C₂₋₄)fluoroalkyl;    -   (C₂₋₅)alkenyl;    -   (C₁₋₄)alkoxy-C(O)—(C₁₋₄)alkylene-;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one or two substituents independently        selected from fluoro, methyl, nitro, or (C₁₋₄)alkoxy-C(O)—NH—;    -   ring^(B1)-X^(B1)—; wherein X^(B1) is a direct bond, or        (C₁₋₄)alkylene- (especially methylene); and wherein ring^(B1) is        a 4- to 6-membered saturated heterocyclyl containing one ring        heteratom which is O (especially oxetanyl), wherein said        ring^(B1) is attached to X^(B1) at a ring carbon atom; wherein        said ring^(B1) is optionally substituted by one substituent        selected from hydroxy, fluoro, (C₁₋₄)alkyl (especially methyl)        or (C₁₋₄)alkoxy (especially methoxy); or    -   ring^(B2)-X^(B2)—; wherein X^(B2) is a direct bond, or        (C₁₋₄)alkylene- (especially methylene); and wherein ring^(B2) is        a 4- to 6-membered saturated heterocyclyl containing one ring        heteratom which is NR^(B)(especially azetidinyl, or        pyrrolidinyl), wherein said ring^(B2) is attached to X^(B2) at a        ring carbon atom; wherein said ring^(B2) is optionally        substituted by one oxo substituent, or by one or two fluoro        substituents; and wherein    -   R^(B) independently represents        -   hydrogen;        -   (C₁₋₄)alkyl;        -   (C₂₋₄)fluoroalkyl;        -   (C₁₋₄)alkyl-C(O)—;        -   (C₁₋₄)alkoxy-C(O)—;        -   (C₁₋₄)alkyl-SO₂—;        -   R^(N7)R^(N8)N—SO₂— wherein R^(N7) and R^(N8) are            independently hydrogen or (C₁₋₄)alkyl;        -   R^(N9)R^(N10)N—C(O)— wherein R^(N9) and R^(N10) are            independently hydrogen or (C₁₋₄)alkyl;        -   Ring^(C)-O—C(O)—, and wherein ring^(C) is (C₃₋₆)cycloalkyl            optionally containing one ring oxygen atom, wherein ring^(C)            is optionally substituted with one R^(C), wherein R^(C) is            (C₁₋₄)alkyl or (C₁₋₄)fluoroalkyl; or        -   Ring^(D), wherein ring^(D) is a 5- to 6-membered heteroaryl            containing 1 to 3 heteroatoms independently selected from O,            N or S (especially 5-membered heteroaryl containing one or            two nitrogen atoms and optionally one further heteroatom            independently selected from nitrogen, oxygen or sulfur),            wherein ring^(D) is unsubstituted or mono-substituted with            R^(D), wherein R^(D) is (C₁₋₄)alkyl or (C₁₋₄)fluoroalkyl.

24) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl (especially methyl);    -   (C₁₋₄)alkyl which is mono-substituted with (C₁₋₄)alkoxy        (especially methoxy, ethoxy), or cyano;    -   (C₂₋₄)alkyl which is mono-substituted with hydroxy;    -   (C₂₋₄)fluoroalkyl (especially 2,2-difluoro-propyl);    -   (C₂₋₅)alkenyl;    -   (C₁₋₄)alkoxy-C(O)—(C₁₋₄)alkylene-;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one or two substituents independently        selected from fluoro, and methyl; [especially such        (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene- is cyclopropyl];    -   ring^(B1)-X^(B1)—; wherein X^(B1) is a direct bond or methylene;        and wherein ring^(B1) is a 4- to 6-membered saturated        heterocyclyl containing one ring heteratom which is 0        (especially oxetanyl), wherein said ring^(B1) is attached to        X^(B1) at a ring carbon atom; wherein said ring^(B1) is        optionally substituted by one substituent selected from hydroxy,        fluoro, or (C₁₋₄)alkyl (especially methyl);    -   ring^(B2)-X^(B2)—; wherein X^(B2) is a direct bond, or        methylene; and wherein ring^(B2) is a 4- to 6-membered saturated        heterocyclyl containing one ring heteratom which is NR^(B)        (especially azetidinyl, or pyrrolidinyl), wherein said ring^(B)        is attached to X^(B2) at a ring carbon atom; wherein said        ring^(B2) is optionally substituted by one oxo substituent, or        by two fluoro substituents; and wherein    -   R^(B) independently represents        -   hydrogen;        -   (C₂₋₄)fluoroalkyl;        -   (C₁₋₄)alkoxy-C(O)—;        -   Ring^(C)-O—C(O)—, and wherein ring^(C) is (C₃₋₆)cycloalkyl            optionally containing one ring oxygen atom, wherein ring^(C)            is optionally substituted with one methyl; or        -   Ring^(D), wherein ring^(D) is a 5- to 6-membered heteroaryl            containing 1 to 3 heteroatoms independently selected from O,            N or S (especially oxadiazolyl), wherein ring^(D) is            unsubstituted or mono-substituted with R^(D), wherein R^(D)            is (C₁₋₄)alkyl or (C₁₋₄)fluoroalkyl.    -   [R⁵ especially represents (C₁₋₄)alkyl (especially methyl);        (C₂₋₄)fluoroalkyl (especially 2,2-difluoro-propyl); or        (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one or two substituents independently        selected from fluoro, and methyl; [especially cyclopropyl];        Examples for such substituents R⁵ are especially methyl,        cyclopropyl and 2,2-difluoro-propyl].

25) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents

-   -   (C₁₋₄)alkyl (especially methyl);    -   (C₁₋₄)alkyl which is mono-substituted with (C₁₋₄)alkoxy        (especially methoxy, ethoxy), or cyano;    -   (C₂₋₄)alkyl which is mono-substituted with hydroxy or        R^(N1)R^(N2)N—, wherein        -   R^(N1) and R^(N2) together with the nitrogen atom form a 4-            to 6-membered saturated ring optionally containing one            further ring heteroatom selected from O and N; wherein said            ring is optionally mono-substituted with (C₁₋₄)alkyl, or            (C₁₋₄)alkoxy;        -   R^(N1) and R^(N2) are independently selected from hydrogen,            (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, or            (C₁₋₄)alkoxy-(C₂₋₄)alkylene;        -   R^(N1) represents (C₁₋₄)alkyl-C(O)—; and R^(N2) represents            hydrogen, or (C₁₋₄)alkyl; or        -   R^(N1) represents phenylsulfonyl-, wherein the phenyl is            optionally substituted by one to three substituents            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, cyano, or nitro; and R^(N2) represents hydrogen, or            (C₁₋₄)alkyl;    -   (C₃₋₄)alkyl which is di-substituted, wherein the substituents        are independently selected from hydroxy, (C₁₋₄)alkoxy, or        R^(N11)R^(N12)N—, wherein R^(N11) and R^(N12) are independently        selected from hydrogen, or (C₁₋₄)alkyl; or    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one or two substituents independently        selected from fluoro, and methyl [especially such        (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene- is cyclopropyl].    -   [Examples for such substituents are methyl, ethyl, isopropyl,        isobutyl, tert-butyl, cyanomethyl, 1-cyanoethyl, 2-cyanopropyl,        1-cyano-1-methyl-ethyl, methoxymethyl, ethoxymethyl,        2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxy-2-methyl-propyl,        2-hydoxy-1,1-dimethyl-ethyl, 2-hydroxy-2-methyl-propyl,        2-(3-methoxy-azetidin-1-yl)-ethyl, 2-pyrrolidin-1-yl-ethyl-,        2-piperidin-1-yl-ethyl-, 2-(4-methyl-piperazin-1-yl)-ethyl-,        2-morpholin-4-yl-ethyl, 2-aminoethyl, 2-amino-propyl,        2-amino-1-methyl-ethyl, 2-methylamino-ethyl,        3-amino-2-methyl-propyl, 2-amino-1,1-dimethyl-ethyl,        2-amino-2-methyl-propyl, 2-cyclopropylamino-ethyl,        cyclopropylmethylamino-ethyl, 2-(isopropyl-methyl-amino)ethyl,        2-[(methoxy-ethyl)-methyl-amino]-ethyl, CH₃C(O)NH—CH₂CH₂—,        2-(4-chloro-phenyl-sulfonylamino)-2-methyl-prop-1-yl,        2-(2-nitro-phenyl-sulfonylamino)-2-methyl-prop-1-yl,        2,3-dihydroxy-propyl, 2-dimethylamino-3-hydroxy-propyl,        2-hydroxy-3-methoxy-propyl, 3-methoxy-2-hydroxy-propyl, and, in        addition, cyclopropyl. Preferred are methyl, ethyl, isopropyl,        isobutyl, tert-butyl, cyanomethyl, 1-cyanoethyl, 2-cyanopropyl,        methoxymethyl, ethoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl,        3-hydroxy-2-methyl-propyl, 2-hydroxy-1,1-dimethyl-ethyl,        2-hydroxy-2-methyl-propyl, 2,3-dihydroxy-propyl,        3-methoxy-2-hydroxy-propyl, 3-methoxy-2-hydroxy-propyl,        2-(3-methoxy-azetidin-1-yl)-ethyl, 2-pyrrolidin-1-yl-ethyl-,        2-piperidin-1-yl-ethyl-, 2-morpholin-4-yl-ethyl,        2-cyclopropylmethylamino-ethyl,        2-[(2-methoxy-ethyl)-methyl-amino]-ethyl,        2-(4-chloro-phenyl-sulfonylamino)-2-methyl-prop-1-yl, and, in        addition, cyclopropyl].

26) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents (C₂₋₄)fluoroalkyl(especially 2,2-difluoro-ethyl, 2,2-difluoro-propyl,2,2-difluoro-1-methyl-ethyl, 2-fluoropropyl, 2-fluoro-2-methyl-propyl;in particular 2,2-difluoro-propyl).

27) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents (C₂₋₅)alkynyl (especially1,1-dimethyl-prop-2-ynyl).

28) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents (C₂₋₄)alkenyl (especiallyisopropenyl, 2-methyl-propenyl, or 2-methyl-allyl).

29) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ representsR^(N3)R^(N4)N—C(O)—(C₀₋₄)alkylene-, wherein R^(N3) and R^(N4)independently are hydrogen or (C₁₋₄)alky (especially (CH₃)₂N—C(O)—,(isobutyl)(methyl)N—C(O)—, H₂N—C(O)CH₂—, H₂N—C(O)—CH(CH₃)—,(CH₃)₂N—C(O)—CH₂— or H₂N—C(O)—C(CH₃)₂—).

30) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents(C₁₋₄)alkoxy-C(O)—(C₀₋₄)alkylene-; (C₁₋₄)alkoxy-C(O)—(C₂₋₄)alkylene-,wherein the (C₂₋₄)alkylene is mono-substituted by R^(N5)R^(N6)N—,wherein R^(N5) and R^(N6) independently are hydrogen or (C₁₋₄)alkyl(especially (CH₃)₂CH—O—C(O)—, (CH₃)₂CHCH₂—O—C(O)—, CH₃O—C(O)—CH₂—,H₃CO—C(O)—C(CH₃)₂—, H₃CO—C(O)—CH(CH₃)CH₂— andCH₃O—C(O)—CH[N(CH₃)₂]—CH₂—).

31) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents(C₁₋₄)alkoxy-C(O)—NH—(C₂₋₄)alkylene-, wherein the (C₂₋₄)alkylene- isoptionally substituted by one to three halogen (especially fluoro).[Examples for such a substituent are 2-(tert-butoxycarbonylamino)-ethyl,and2,2,2-trifluoro-(1-(tert-butyloxycarbonyl-amino)-1-(methyl)-ethan-1-yl).

32) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents(C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is optionallysubstituted by one or two substituents independently selected fromfluoro, (C₁₋₄)alkyl, nitro, or (C₁₋₄)alkoxy-C(O)—NH— (especially fluoro,methyl) [examples for (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene- are especiallycyclopropyl, cyclopropylmethyl, 1-fluoro-cyclopropyl-methyl,1-methyl-cyclopropyl-methyl, 2,2-difluoro-cyclopropylmethyl; inparticular cyclopropyl].

33) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents ring^(B)-X^(B)—; whereinX^(B) is a direct bond, or (C₁₋₄)alkylene- (especially methylene); andwherein ring^(B) is a 4- to 6-membered saturated heterocyclyl containingone or two ring heteratom independently selected from O, S, and NR^(B),wherein said ring^(B) is attached to X^(B) at a ring carbon atom(especially oxetan-3-yl, azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, piperidin-4-yl);

-   -   wherein said ring^(B) is optionally substituted by one or two        substituents selected from oxo, hydroxy, fluoro, (C₁₋₄)alkyl        (especially methyl, ethyl), or (C₁₋₄)alkoxy (especially        methoxy); (such that ring^(B) is especially oxetan-3-yl,        3-fluoro-oxetan-3-yl, 3-methyl-oxetan-3-yl,        3-methoxy-oxetan-3-yl, 3-hydroxy-oxetan-3-yl, azetidin-2-yl,        azetidin-3-yl, 2-oxo-azetidin-3-yl, pyrrolidin-2-yl,        pyrrolidin-3-yl, 2-oxo-pyrrolidin-3-yl,        4,4-difluoro-pyrrolidin-2-yl, piperidin-4-yl); and wherein    -   R^(B) independently represents        -   hydrogen;        -   (C₁₋₄)alkyl (especially methyl, ethyl, isopropyl, isobutyl);        -   (C₂₋₄)fluoroalkyl (especially 2-fluoroethyl,            2,2-difluoroethyl);        -   (C₁₋₄)alkyl-C(O)— (especially methylcarbonyl-,            isopropylcarbonyl-);        -   (C₁₋₄)alkoxy-C(O)— (especially methoxycarbonyl-,            ethoxycarbonyl-, isopropoxycarbonyl-, isobutoxycarbonyl,            tert-butoxycarbonyl);        -   (C₁₋₄)alkyl-SO₂— (especially methylsulfonyl);        -   R^(N7)R^(N8)N—SO₂— wherein R^(N7) and R^(N8) are            independently hydrogen or (C₁₋₄)alkyl (especially methyl);        -   R^(N9)R^(N10)N—C(O)— wherein R^(N9) and R^(N10) are            independently hydrogen or (C₁₋₄)alkyl (especially methyl);        -   Ring^(C)-O—C(O)—, and wherein ring^(C) is (C₃₋₆)cycloalkyl            optionally containing one ring oxygen atom (especially            oxetan-3-yl), wherein ring^(C) is optionally substituted            with one R^(C), wherein R^(C) is (C₁₋₄)alkyl or            (C₁₋₄)fluoroalkyl (especially methyl, or trifluoromethyl);            or        -   Ring^(D), wherein ring^(D) is a 5- to 6-membered heteroaryl            containing 1 to 3 heteroatoms independently selected from O,            N or S (especially [1,3,4]oxadiazol-2-yl), wherein ring^(D)            is unsubstituted or mono-substituted with R^(D), wherein            R^(D) is (C₁₋₄)alkyl or (C₁₋₄)fluoroalkyl (especially            methyl, isopropyl, or trifluoromethyl).    -   [Examples for such groups ring^(B)-X^(B)— according to        embodiment 33) are 3-hydroxy-oxetan-3-yl, 3-fluoro-oxetan-3-yl,        3-methyl-oxetan-3-yl, 2-oxo-azetidin-3-yl,        1-ethyl-azetidin-3-yl, 1-(2-fluoro-ethyl)-azetidin-3-yl,        1-(2,2-difluoro-ethyl)azetidin-3-yl, 1-isopropyl-azetidin-3-yl,        1-methylcarbonyl-azetidin-3-yl,        1-methylaminocarbonyl-azetidin-3-yl, 1-isobutyl-azetidin-3-yl,        1-methylsulfonyl-azetidin-3-yl, methoxycarbonyl-azetidin-3-yl,        1-dimethylaminocarbonyl-azetidin-3-yl,        1-1-ethoxycarbonyl-azetidin-3-yl,        1-isopropoxycarbonyl-azetidin-3-yl,        1-isobutoxycarbonyl-azetidin-3-yl,        1-isopropylcarbonyl-azetidin-3-yl,        1-tert-butoxycarbonyl-azetidin-3-yl,        1-dimethylaminosulfonyl-azetidin-3-yl,        1-(5-methyl-[1,3,4]oxadiazol-2-yl)-azetidin-3-yl,        1-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-azetidin-3-yl,        1-(5-trifluoromethyl-[1,3,4]-oxadiazol-2-yl)-azetidin-3-yl,        1-(oxetan-3-yl-oxycarbonyl)-azetidin-3-yl,        1-(3-methyl-oxetan-3-oxycarbonyl)-azetidin-3-yl,        1-(3-trifluoromethyl-oxetan-3-yl-oxycarbonyl)-azetidin-3-yl,        azetidin-2-yl-methyl-, 1-methylcarbonyl-azetidin-2-ylmethyl,        1-methoxycarbonyl-azetidin-2-ylmethyl,        1-ethoxycarbonyl-azetidin-3-ylmethyl,        1-isopropoxycarbonyl-azetidin-3-ylmethyl-,        1-tert-butoxycarbonyl-azetidin-2-ylmethyl,        1-methyl-2-oxo-pyrrolidin-3-yl,        1-methylcarbonyl-pyrrolidin-3-yl,        1-isopropyl-2-oxo-pyrrolidin-3-yl,        1-tert-butoxycarbonyl-pyrrolidin3-yl, pyrrolidin-2-yl-methyl-,        4,4-difluoro-pyrrolidin-2yl-methyl-,        1-methylcarbonyl-pyrrolidin-2-yl-methyl-,        1-tert-butoxycarbonyl-pyrrolidin-2-ylmethyl-, and        1-tert-butoxycarbonyl-4,4-di-fluoro-pyrrolidin-2-yl-methyl-.        Preferred examples are 1-(2,2-difluoro-ethyl)azetidin-3-yl,        4,4-difluoro-azetidin-2-yl-methyl,        1-methoxycarbonyl-azetidin-2-ylmethyl,        1-isobutoxycarbonyl-azetidin-3-yl,        1-tert-butoxycarbonyl-azetidin-3-yl,        1-isopropoxycarbonyl-azetidin-2-yl-methyl,        1-tert-butoxycarbonyl-azetidin-2-ylmethyl,        1-tert-butoxycarbonyl-4,4-difluoro-azetidin-2-ylmethyl,        1-isopropoxycarbonyl-azetidin-3-yl,        1-ethoxycarbonyl-azetidin-2-yl-methyl,        1-ethoxycarbonyl-azetidin-3-yl, 2-oxo-azetidin-3-yl,        oxetan-3-yl, 3-methyl-oxetan-3-yl-methyl,        3-hydroxy-oxetan-3-ylmethyl, 3-fluoro-oxetan-3-yl-methyl,        3-trifluoromethyl-oxetan-3-yl-methyl,        1-tert-butoxycarbonyl-pyrrolidin-3-yl,        4,4-difluoro-pyrrolidin-2-ylmethyl,        1-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-azetidin-3-yl,        1-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-azetidin-3-yl,        1-(3-trifluoromethyl-oxetan-3-yl-oxycarbonyl)-azetidin-3-yl,        1-(3-methyl-oxetan-3-oxycarbonyl)-azetidin-3-yl, and        1-(oxetan-3-yl-oxycarbonyl)-azetidin-3-yl.]

34) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents hydrogen.

35) Another embodiment relates to compounds according to any one ofembodiments 1) to 21), wherein R⁵ represents (C₁₋₄)alkyl (in particularmethyl).

36) Another embodiment relates to compounds according to any one ofembodiments 1) to 35), wherein R⁶ represents hydrogen; (C₁₋₄)alkyl; or(C₁₋₄)fluoroalkyl (especially R⁶ represents hydrogen or methyl).

37) Another embodiment relates to compounds according to any one ofembodiments 1) to 36), wherein R⁷ represents hydrogen, (C₁₋₄)alkyl(especially methyl), or (CH₃)₃Si—CH₂CH₂OCH₂—.

38) Another embodiment relates to compounds according to any one ofembodiments 1) to 37), wherein R⁸ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl (especially methyl);    -   (C₂₋₄)fluoroalkyl (especially 2-fluoro-2-methyl-propyl,        2,2-difluoro-propyl);    -   (C₃₋₆)cycloalkyl or (C₃₋₆)cycloalkyl-methyl-, wherein the        cycloalkyl is unsubstituted or mono-substituted with methyl        (especially cyclopropyl, cyclopropylmethyl,        1-methyl-cyclopropyl-methyl-);    -   (C₁₋₄)alkoxy-C(O)-methylene- (especially        methoxycarbonylmethyl-); or    -   CH₃)₃Si—CH₂CH₂OCH₂—.

39) The invention, thus, especially relates to compounds of the formula(I) as defined in embodiment 1), and to such compounds further limitedby the characteristics of any one of embodiments 2) to 38), underconsideration of their respective dependencies; to pharmaceuticallyacceptable salts thereof; and to the use of such compounds asmedicaments especially for use in the prevention/prophylaxis ortreatment of diseases and disorders related to pathogenic eventsassociated with elevated levels of C5a and/or with C5aR activation.

For avoidance of any doubt, especially the following embodimentsrelating to the compounds of formula (I) are thus possible and intendedand herewith specifically disclosed in individualized form:

1, 2+1, 4+1, 4+2+1, 5+1, 5+2+1, 9+1, 9+2+1, 9+4+1, 9+4+2+1, 9+5+1,9+5+2+1, 13+1, 13+2+1, 13+4+1, 13+4+2+1, 13+5+1, 13+5+2+1, 14+1, 14+2+1,14+4+1, 14+4+2+1, 14+5+1, 14+5+2+1, 15+1, 15+2+1, 15+4+1, 15+4+2+1,15+5+1, 15+5+2+1, 16+1, 16+2+1, 16+4+1, 16+4+2+1, 16+5+1, 16+5+2+1,16+9+1, 16+9+2+1, 16+9+4+1, 16+9+4+2+1, 16+9+5+1, 16+9+5+2+1, 16+13+1,16+13+2+1, 16+13+4+1, 16+13+4+2+1, 16+13+5+1, 16+13+5+2+1, 16+14+1,16+14+2+1, 16+14+4+1, 16+14+4+2+1, 16+14+5+1, 16+14+5+2+1, 16+15+1,16+15+2+1, 16+15+4+1, 16+15+4+2+1, 16+15+5+1, 16+15+5+2+1, 18+1, 18+2+1,18+4+1, 18+4+2+1, 18+5+1, 18+5+2+1, 18+9+1, 18+9+2+1, 18+9+4+1,18+9+4+2+1, 18+9+5+1, 18+9+5+2+1, 18+13+1, 18+13+2+1, 18+13+4+1,18+13+4+2+1, 18+13+5+1, 18+13+5+2+1, 18+14+1, 18+14+2+1, 18+14+4+1,18+14+4+2+1, 18+14+5+1, 18+14+5+2+1, 18+15+1, 18+15+2+1, 18+15+4+1,18+15+4+2+1, 18+15+5+1, 18+15+5+2+1, 19+1, 19+2+1, 19+4+1, 19+4+2+1,19+5+1, 19+5+2+1, 19+9+1, 19+9+2+1, 19+9+4+1, 19+9+4+2+1, 19+9+5+1,19+9+5+2+1, 19+13+1, 19+13+2+1, 19+13+4+1, 19+13+4+2+1, 19+13+5+1,19+13+5+2+1, 19+14+1, 19+14+2+1, 19+14+4+1, 19+14+4+2+1, 19+14+5+1,19+14+5+2+1, 19+15+1, 19+15+2+1, 19+15+4+1, 19+15+4+2+1, 19+15+5+1,19+15+5+2+1, 23+1, 23+2+1, 23+4+1, 23+4+2+1, 23+5+1, 23+5+2+1, 23+9+1,23+9+2+1, 23+9+4+1, 23+9+4+2+1, 23+9+5+1, 23+9+5+2+1, 23+13+1,23+13+2+1, 23+13+4+1, 23+13+4+2+1, 23+13+5+1, 23+13+5+2+1, 23+14+1,23+14+2+1, 23+14+4+1, 23+14+4+2+1, 23+14+5+1, 23+14+5+2+1, 23+15+1,23+15+2+1, 23+15+4+1, 23+15+4+2+1, 23+15+5+1, 23+15+5+2+1, 23+16+1,23+16+2+1, 23+16+4+1, 23+16+4+2+1, 23+16+5+1, 23+16+5+2+1, 23+16+9+1,23+16+9+2+1, 23+16+9+4+1, 23+16+9+4+2+1, 23+16+9+5+1, 23+16+9+5+2+1,23+16+13+1, 23+16+13+2+1, 23+16+13+4+1, 23+16+13+4+2+1, 23+16+13+5+1,23+16+13+5+2+1, 23+16+14+1, 23+16+14+2+1, 23+16+14+4+1, 23+16+14+4+2+1,23+16+14+5+1, 23+16+14+5+2+1, 23+16+15+1, 23+16+15+2+1, 23+16+15+4+1,23+16+15+4+2+1, 23+16+15+5+1, 23+16+15+5+2+1, 23+18+1, 23+18+2+1,23+18+4+1, 23+18+4+2+1, 23+18+5+1, 23+18+5+2+1, 23+18+9+1, 23+18+9+2+1,23+18+9+4+1, 23+18+9+4+2+1, 23+18+9+5+1, 23+18+9+5+2+1, 23+18+13+1,23+18+13+2+1, 23+18+13+4+1, 23+18+13+4+2+1, 23+18+13+5+1,23+18+13+5+2+1, 23+18+14+1, 23+18+14+2+1, 23+18+14+4+1, 23+18+14+4+2+1,23+18+14+5+1, 23+18+14+5+2+1, 23+18+15+1, 23+18+15+2+1, 23+18+15+4+1,23+18+15+4+2+1, 23+18+15+5+1, 23+18+15+5+2+1, 23+19+1, 23+19+2+1,23+19+4+1, 23+19+4+2+1, 23+19+5+1, 23+19+5+2+1, 23+19+9+1, 23+19+9+2+1,23+19+9+4+1, 23+19+9+4+2+1, 23+19+9+5+1, 23+19+9+5+2+1, 23+19+13+1,23+19+13+2+1, 23+19+13+4+1, 23+19+13+4+2+1, 23+19+13+5+1,23+19+13+5+2+1, 23+19+14+1, 23+19+14+2+1, 23+19+14+4+1, 23+19+14+4+2+1,23+19+14+5+1, 23+19+14+5+2+1, 23+19+15+1, 23+19+15+2+1, 23+19+15+4+1,23+19+15+4+2+1, 23+19+15+5+1, 23+19+15+5+2+1, 24+1, 24+2+1, 24+4+1,24+4+2+1, 24+5+1, 24+5+2+1, 24+9+1, 24+9+2+1, 24+9+4+1, 24+9+4+2+1,24+9+5+1, 24+9+5+2+1, 24+13+1, 24+13+2+1, 24+13+4+1, 24+13+4+2+1,24+13+5+1, 24+13+5+2+1, 24+14+1, 24+14+2+1, 24+14+4+1, 24+14+4+2+1,24+14+5+1, 24+14+5+2+1, 24+15+1, 24+15+2+1, 24+15+4+1, 24+15+4+2+1,24+15+5+1, 24+15+5+2+1, 24+16+1, 24+16+2+1, 24+16+4+1, 24+16+4+2+1,24+16+5+1, 24+16+5+2+1, 24+16+9+1, 24+16+9+2+1, 24+16+9+4+1,24+16+9+4+2+1, 24+16+9+5+1, 24+16+9+5+2+1, 24+16+13+1, 24+16+13+2+1,24+16+13+4+1, 24+16+13+4+2+1, 24+16+13+5+1, 24+16+13+5+2+1, 24+16+14+1,24+16+14+2+1, 24+16+14+4+1, 24+16+14+4+2+1, 24+16+14+5+1,24+16+14+5+2+1, 24+16+15+1, 24+16+15+2+1, 24+16+15+4+1, 24+16+15+4+2+1,24+16+15+5+1, 24+16+15+5+2+1, 24+18+1, 24+18+2+1, 24+18+4+1,24+18+4+2+1, 24+18+5+1, 24+18+5+2+1, 24+18+9+1, 24+18+9+2+1,24+18+9+4+1, 24+18+9+4+2+1, 24+18+9+5+1, 24+18+9+5+2+1, 24+18+13+1,24+18+13+2+1, 24+18+13+4+1, 24+18+13+4+2+1, 24+18+13+5+1,24+18+13+5+2+1, 24+18+14+1, 24+18+14+2+1, 24+18+14+4+1, 24+18+14+4+2+1,24+18+14+5+1, 24+18+14+5+2+1, 24+18+15+1, 24+18+15+2+1, 24+18+15+4+1,24+18+15+4+2+1, 24+18+15+5+1, 24+18+15+5+2+1, 24+19+1, 24+19+2+1,24+19+4+1, 24+19+4+2+1, 24+19+5+1, 24+19+5+2+1, 24+19+9+1, 24+19+9+2+1,24+19+9+4+1, 24+19+9+4+2+1, 24+19+9+5+1, 24+19+9+5+2+1, 24+19+13+1,24+19+13+2+1, 24+19+13+4+1, 24+19+13+4+2+1, 24+19+13+5+1,24+19+13+5+2+1, 24+19+14+1, 24+19+14+2+1, 24+19+14+4+1, 24+19+14+4+2+1,24+19+14+5+1, 24+19+14+5+2+1, 24+19+15+1, 24+19+15+2+1, 24+19+15+4+1,24+19+15+4+2+1, 24+19+15+5+1, 24+19+15+5+2+1, 26+1, 26+2+1, 26+4+1,26+4+2+1, 26+5+1, 26+5+2+1, 26+9+1, 26+9+2+1, 26+9+4+1, 26+9+4+2+1,26+9+5+1, 26+9+5+2+1, 26+13+1, 26+13+2+1, 26+13+4+1, 26+13+4+2+1,26+13+5+1, 26+13+5+2+1, 26+14+1, 26+14+2+1, 26+14+4+1, 26+14+4+2+1,26+14+5+1, 26+14+5+2+1, 26+15+1, 26+15+2+1, 26+15+4+1, 26+15+4+2+1,26+15+5+1, 26+15+5+2+1, 26+16+1, 26+16+2+1, 26+16+4+1, 26+16+4+2+1,26+16+5+1, 26+16+5+2+1, 26+16+9+1, 26+16+9+2+1, 26+16+9+4+1,26+16+9+4+2+1, 26+16+9+5+1, 26+16+9+5+2+1, 26+16+13+1, 26+16+13+2+1,26+16+13+4+1, 26+16+13+4+2+1, 26+16+13+5+1, 26+16+13+5+2+1, 26+16+14+1,26+16+14+2+1, 26+16+14+4+1, 26+16+14+4+2+1, 26+16+14+5+1,26+16+14+5+2+1, 26+16+15+1, 26+16+15+2+1, 26+16+15+4+1, 26+16+15+4+2+1,26+16+15+5+1, 26+16+15+5+2+1, 26+18+1, 26+18+2+1, 26+18+4+1,26+18+4+2+1, 26+18+5+1, 26+18+5+2+1, 26+18+9+1, 26+18+9+2+1,26+18+9+4+1, 26+18+9+4+2+1, 26+18+9+5+1, 26+18+9+5+2+1, 26+18+13+1,26+18+13+2+1, 26+18+13+4+1, 26+18+13+4+2+1, 26+18+13+5+1,26+18+13+5+2+1, 26+18+14+1, 26+18+14+2+1, 26+18+14+4+1, 26+18+14+4+2+1,26+18+14+5+1, 26+18+14+5+2+1, 26+18+15+1, 26+18+15+2+1, 26+18+15+4+1,26+18+15+4+2+1, 26+18+15+5+1, 26+18+15+5+2+1, 26+19+1, 26+19+2+1,26+19+4+1, 26+19+4+2+1, 26+19+5+1, 26+19+5+2+1, 26+19+9+1, 26+19+9+2+1,26+19+9+4+1, 26+19+9+4+2+1, 26+19+9+5+1, 26+19+9+5+2+1, 26+19+13+1,26+19+13+2+1, 26+19+13+4+1, 26+19+13+4+2+1, 26+19+13+5+1,26+19+13+5+2+1, 26+19+14+1, 26+19+14+2+1, 26+19+14+4+1, 26+19+14+4+2+1,26+19+14+5+1, 26+19+14+5+2+1, 26+19+15+1, 26+19+15+2+1, 26+19+15+4+1,26+19+15+4+2+1, 26+19+15+5+1, 26+19+15+5+2+1.

In the list above the numbers refer to the embodiments according totheir numbering provided hereinabove whereas “+” indicates thedependency from another embodiment. The different individualizedembodiments are separated by commas. In other words, “26+18+14+1” forexample refers to embodiment 26) depending on embodiment 18), dependingon embodiment 14), depending on embodiment 1), i.e. embodiment“26+18+14+1” corresponds to the compounds of formula (I) according toembodiment 1) further limited by all the features of the embodiments14), 18), and 26).

40) A second aspect of the invention relates to compounds of the formula(I) according to embodiment 1), which are also compounds of the formula(II)

wherein

-   -   Y represents NR⁵; and X and Z independently represent N or CH        (notably Y represents NR⁵; one of X and Z represents N, and the        other of X and Z represents N or CH);    -   Y represents CR⁶; one of X and Z represents NR⁷, O or S, and the        other of X and Z represents N; or    -   Y represents N; one of X and Z represents NR⁸, and the other of        X and Z represents N or CH;

ring A represents a saturated 4- to 7-membered mono-cyclic carbocyclicring containing the ring nitrogen atom to which R¹ is attached, whereinsaid ring A is optionally mono-substituted with R^(A); wherein R^(A)represents (C₁₋₄)alkyl (especially methyl) [preferably ring A issubstituted with R¹ and carries no further substituent (i.e. R^(A) isabsent)];

R¹ represents phenyl; 5-membered heteroaryl, or 6-membered heteroarylwherein said phenyl, 5-membered heteroaryl or 6-membered heteroarylindependently is mono-, di- or tri-substituted, wherein the substituentsare independently selected from (C₁₋₄)alkyl; (C₁₋₄)alkoxy;(C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy; halogen; cyano; or(C₃₋₆)cycloalkyl;

R² represents phenyl, 5-membered heteroaryl, or 6-membered heteroaryl;wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroarylindependently is mono-, or di-, or tri-substituted, wherein thesubstituents are independently selected from

-   -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy;    -   (C₁₋₃)fluoroalkyl;    -   (C₁₋₃)fluoroalkoxy;    -   halogen;    -   (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,        —O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl        optionally contains one ring oxygen atom; or    -   R^(21a)R^(21b)N—, wherein R^(21a) and R^(21b) independently        represent hydrogen or (C₁₋₄)alkyl;

R³ represents hydrogen or (C₁₋₃)alkyl (especially hydrogen);

R⁵ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkyl which is mono-substituted with hydroxy,        (C₁₋₄)alkoxy, cyano, or R^(N1)R^(N2)N—, wherein        -   R^(N1) and R^(N2) together with the nitrogen atom form a 4-            to 6-membered saturated ring optionally containing one            further ring heteroatom selected from O and N; wherein said            ring is optionally mono-substituted with (C₁₋₄)alkyl, or            (C₁₋₄)alkoxy;        -   R^(N1) and R^(N2) are independently selected from hydrogen,            (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, or            (C₁₋₄)alkoxy-(C₂₋₄)alkylene;        -   R^(N1) represents (C₁₋₄)alkyl-C(O)—; and R^(N2) represents            hydrogen, or (C₁₋₄)alkyl; or        -   R^(N1) represents phenylsulfonyl-, wherein the phenyl is            optionally substituted by one to three substituents            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, cyano, or nitro; and R^(N2) represents hydrogen, or            (C₁₋₄)alkyl;    -   (C₂₋₄)alkyl which is di- or tri-substituted, wherein the        substituents are independently selected from hydroxy,        (C₁₋₄)alkoxy, or R^(N1)R^(N2)N—, wherein        -   R^(N1) and R^(N2) together with the nitrogen atom form a 4-            to 6-membered saturated ring; or        -   R^(N1) and R^(N2) are independently selected from hydrogen,            or (C₁₋₄)alkyl;    -   (C₂₋₄)fluoroalkyl;    -   (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-;    -   (C₂₋₅)alkynyl;    -   (C₂₋₅)alkenyl;    -   R^(N3)R^(N4)N—C(O)—(C₀₋₄)alkylene-, wherein R^(N3) and R^(N4)        independently are hydrogen or (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy-C(O)—(C₀₋₄)alkylene-;    -   (C₁₋₄)alkoxy-C(O)—(C₂₋₄)alkylene-, wherein the (C₂₋₄)alkylene is        mono-substituted by R^(N5)R^(N6)N—, wherein R^(N5) and R^(N6)        independently are hydrogen or (C₁₋₄)alkyl    -   (C₁₋₄)alkoxy-C(O)—(C₂₋₄)alkylene-, wherein the (C₂₋₄)alkylene is        substituted by one to three halogen;    -   (C₁₋₄)alkoxy-C(O)—NH—(C₂₋₄)alkylene-, wherein the        (C₂₋₄)alkylene- is optionally substituted by one to three        halogen;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one or two substituents independently        selected from fluoro, (C₁₋₄)alkyl, nitro, or        (C₁₋₄)alkoxy-C(O)—NH—; or    -   ring^(B)-X^(B)—; wherein X^(B) is a direct bond, or        (C₁₋₄)alkylene-; and wherein ring^(B) is a 4- to 6-membered        saturated heterocyclyl containing one or two ring heteratom        independently selected from O, S, and NR^(B), wherein said        ring^(B) is attached to X^(B) at a ring carbon atom;    -   wherein said ring^(B) is optionally substituted by one or two        substituents independently selected from oxo, hydroxy, fluoro,        (C₁₋₄)alkyl or (C₁₋₄)alkoxy; and wherein    -   R^(B) independently represents        -   hydrogen;        -   (C₁₋₄)alkyl;        -   (C₂₋₄)fluoroalkyl;        -   (C₁₋₄)alkyl-C(O)—;        -   (C₁₋₄)alkoxy-C(O)—;        -   (C₁₋₄)alkyl-SO₂—;        -   R^(N7)R^(N8)N—SO₂— wherein R^(N7) and R^(N8) are            independently hydrogen or (C₁₋₄)alkyl;        -   R^(N9)R^(N10)N—C(O)— wherein R^(N9) and R^(N10) are            independently hydrogen or (C₁₋₄)alkyl;        -   Ring^(C)-O—C(O)—, and wherein ring^(C) is (C₃₋₆)cycloalkyl            optionally containing one ring oxygen atom, wherein ring^(C)            is optionally substituted with one R^(C), wherein R^(C) is            (C₁₋₄)alkyl or (C₁₋₄)fluoroalkyl; or        -   Ring^(D), wherein ring^(D) is a 5- to 6-membered heteroaryl            containing 1 to 3 heteroatoms independently selected from O,            N or S, wherein ring^(D) is unsubstituted or            mono-substituted with R^(D), wherein R^(D) is (C₁₋₄)alkyl or            (C₁₋₄)fluoroalkyl;

R⁶ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₁₋₄)fluoroalkyl; or    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one to three substituents        independently selected from halogen or (C₁₋₄)alkyl;

R⁷ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl; or    -   (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-; and

R⁸ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₂₋₄)fluoroalkyl;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one to three substituents        independently selected from halogen or (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy-C(O)—(C₁₋₄)alkylene-; or    -   (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-;

wherein the characteristics disclosed in embodiments 2) to 38),especially as specifically listed in embodiment 39), are intended toapply mutatis mutandis also to the compounds of formula (II) accordingto embodiment 40).

41) Another embodiment relates to compounds of formula (II) according toembodiment 40), wherein

Y represents NR⁵; and X and Z independently represent N or CH (notably Yrepresents NR⁵; one of X and Z represents N, and the other of X and Zrepresents N or CH);

ring A represents an unsubstituted saturated 4- to 7-memberedmono-cyclic carbocyclic ring containing the ring nitrogen atom to whichR¹ is attached [for avoidance of doubt, said ring A is substituted withR¹ and carries no further substituent (i.e. R^(A) is absent)] [notablyring A represents pyrrolidin-1-3-diyl, or piperidin-1,4-diyl; especiallypiperidin-1,4-diyl];

R¹ represents phenyl, or 6-membered heteroaryl wherein said phenyl, or6-membered heteroaryl independently is mono-, di- or tri-substituted,wherein the substituents are independently selected from (C₁₋₄)alkyl;(C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy; halogen; cyano; or(C₃₋₆)cycloalkyl; [notably R¹ represents phenyl or pyridinyl, whichphenyl or pyridinyl independently is mono- or di-substituted wherein thesubstituents are independently selected from (C₁₋₄)alkyl (especiallymethyl); (C₁₋₄)alkoxy (especially methoxy); (C₁₋₃)fluoroalkyl(especially trifluoromethyl, or difluoromethyl); (C₁₋₃)fluoroalkoxy(especially trifluoromethoxy); halogen (especially fluoro or chloro);cyano; or (C₃₋₆)cycloalkyl (especially cyclopropyl)];

R² represents phenyl, or pyridinyl; wherein said phenyl or pyridinylindependently is mono-, or di-, or tri-substituted, wherein thesubstituents are independently selected from

-   -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy;    -   (C₁₋₃)fluoroalkyl;    -   (C₁₋₃)fluoroalkoxy;    -   halogen; or    -   (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,        —O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl        optionally contains one ring oxygen atom;    -   [notably R² represents phenyl or pyridinyl, wherein said phenyl        or pyridinyl independently is mono- or di-substituted wherein        the substituents are independently selected from (C₁₋₄)alkyl;        (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        (C₁₋₃)fluoroalkoxy; halogen; (C₃₋₆)cycloalkyl;        (C₃₋₆)cycloalkyl-O—; and (C₃₋₆)cycloalkyl-CH₂—O—; in particular        R² represents phenyl, which is mono-substituted with        trifluoromethyl];

R³ represents hydrogen;

R⁵ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkyl which is mono-substituted with hydroxy,        (C₁₋₄)alkoxy, cyano;    -   (C₂₋₄)fluoroalkyl;    -   (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-;    -   (C₂₋₅)alkenyl;    -   (C₁₋₄)alkoxy-C(O)—(C₀₋₄)alkylene-;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one or two substituents independently        selected from fluoro, (C₁₋₄)alkyl, nitro, or        (C₁₋₄)alkoxy-C(O)—NH—.    -   ring^(B)-X^(B)—; wherein X^(B) is a direct bond, or        (C₁₋₄)alkylene-; and wherein ring^(B) is a 4-membered saturated        heterocyclyl containing one ring heteratom selected from O and        NR^(B), wherein said ring^(B) is attached to X^(B) at a ring        carbon atom;    -   wherein said ring^(B) is optionally substituted by one        substituent selected from fluoro, (C₁₋₄)alkyl; and wherein    -   R^(B) independently represents        -   (C₁₋₄)alkoxy-C(O)—;        -   Ring^(D), wherein ring^(D) is a 5- to 6-membered heteroaryl            containing 1 to 3 heteroatoms independently selected from O,            N or S, wherein ring^(D) is unsubstituted or            mono-substituted with R^(D), wherein R^(D) is (C₁₋₄)alkyl or            (C₁₋₄)fluoroalkyl;    -   [notably R⁵ represents (C₁₋₄)alkyl (especially methyl);        (C₂₋₄)fluoroalkyl (especially 2,2-difluoro-propyl), or        (C₃₋₆)cycloalkyl (especially cyclopropyl)].

42) A third aspect of the invention relates to compounds of the formula(I) according to embodiment 1), which are also compounds of the formula(III)

wherein

-   -   Y represents NR⁵; and X and Z independently represent N or CH        (notably Y represents NR⁵; one of X and Z represents N, and the        other of X and Z represents N or CH);    -   Y represents CR⁶; one of X and Z represents NR⁷, O or S, and the        other of X and Z represents N; or    -   Y represents N; one of X and Z represents NR⁸, and the other of        X and Z represents N or CH;

ring A represents a saturated 4- to 7-membered mono-cyclic carbocyclicring containing the ring nitrogen atom to which R¹ is attached, whereinsaid ring A is optionally mono-substituted with R^(A); wherein R^(A)represents (C₁₋₄)alkyl (especially methyl) [preferably ring A issubstituted with R¹ and carries no further substituent (i.e. R^(A) isabsent)];

R¹ represents phenyl; 5-membered heteroaryl, or 6-membered heteroarylwherein said phenyl, 5-membered heteroaryl or 6-membered heteroarylindependently is mono-, di- or tri-substituted, wherein the substituentsare independently selected from (C₁₋₄)alkyl; (C₁₋₄)alkoxy;(C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy; halogen; cyano; or(C₃₋₆)cycloalkyl;

R² represents phenyl, 5-membered heteroaryl, or 6-membered heteroaryl;wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroarylindependently is mono-, or di-, or tri-substituted, wherein thesubstituents are independently selected from

-   -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy;    -   (C₁₋₃)fluoroalkyl;    -   (C₁₋₃)fluoroalkoxy;    -   halogen;    -   (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,        —O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl        optionally contains one ring oxygen atom; or    -   R^(21a)R^(21b)N—, wherein R^(21a) and R^(21b) independently        represent hydrogen or (C₁₋₄)alkyl;

R³ represents hydrogen or (C₁₋₃)alkyl (especially hydrogen);

R⁵ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkyl which is mono-substituted with hydroxy,        (C₁₋₄)alkoxy, cyano, or R^(N1)R^(N2)N—, wherein        -   R^(N1) and R^(N2) together with the nitrogen atom form a 4-            to 6-membered saturated ring optionally containing one            further ring heteroatom selected from O and N; wherein said            ring is optionally mono-substituted with (C₁₋₄)alkyl, or            (C₁₋₄)alkoxy;        -   R^(N1) and R^(N2) are independently selected from hydrogen,            (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, or            (C₁₋₄)alkoxy-(C₂₋₄)alkylene;        -   R^(N1) represents (C₁₋₄)alkyl-C(O)—; and R^(N2) represents            hydrogen, or (C₁₋₄)alkyl; or        -   R^(N1) represents phenylsulfonyl-, wherein the phenyl is            optionally substituted by one to three substituents            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, cyano, or nitro; and R^(N2) represents hydrogen, or            (C₁₋₄)alkyl;    -   (C₂₋₄)alkyl which is di- or tri-substituted, wherein the        substituents are independently selected from hydroxy,        (C₁₋₄)alkoxy, or R^(N1)R^(N2)N—, wherein        -   R^(N1) and R^(N2) together with the nitrogen atom form a 4-            to 6-membered saturated ring; or        -   R^(N1) and R^(N2) are independently selected from hydrogen,            or (C₁₋₄)alkyl;    -   (C₂₋₄)fluoroalkyl;    -   (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-;    -   (C₂₋₅)alkynyl;    -   (C₂₋₅)alkenyl;    -   R^(N3)R^(N4)N—C(O)—(C₀₋₄)alkylene-, wherein R^(N3) and R^(N4)        independently are hydrogen or (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy-C(O)—(C₀₋₄)alkylene-;    -   (C₁₋₄)alkoxy-C(O)—(C₂₋₄)alkylene-, wherein the (C₂₋₄)alkylene is        mono-substituted by R^(N5)R^(N6)N—, wherein R^(N5) and R^(N6)        independently are hydrogen or (C₁₋₄)alkyl    -   (C₁₋₄)alkoxy-C(O)—(C₂₋₄)alkylene-, wherein the (C₂₋₄)alkylene is        substituted by one to three halogen;    -   (C₁₋₄)alkoxy-C(O)—NH—(C₂₋₄)alkylene-, wherein the        (C₂₋₄)alkylene- is optionally substituted by one to three        halogen;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one or two substituents independently        selected from fluoro, (C₁₋₄)alkyl, nitro, or        (C₁₋₄)alkoxy-C(O)—NH—; or    -   ring^(B)-X^(B)—; wherein X^(B) is a direct bond, or        (C₁₋₄)alkylene-; and wherein ring^(B) is a 4- to 6-membered        saturated heterocyclyl containing one or two ring heteratom        independently selected from O, S, and NR^(B), wherein said        ring^(B) is attached to X^(B) at a ring carbon atom;    -   wherein said ring^(B) is optionally substituted by one or two        substituents independently selected from oxo, hydroxy, fluoro,        (C₁₋₄)alkyl or (C₁₋₄)alkoxy; and wherein    -   R^(B) independently represents        -   hydrogen;        -   (C₁₋₄)alkyl;        -   (C₂₋₄)fluoroalkyl;        -   (C₁₋₄)alkyl-C(O)—;        -   (C₁₋₄)alkoxy-C(O)—;        -   (C₁₋₄)alkyl-SO₂—;        -   R^(N7)R^(N8)N—SO₂— wherein R^(N7) and R^(N8) are            independently hydrogen or (C₁₋₄)alkyl;        -   R^(N9)R^(N10)N—C(O)— wherein R^(N9) and R^(N10) are            independently hydrogen or (C₁₋₄)alkyl;        -   Ring^(C)-O—C(O)—, and wherein ring^(C) is (C₃₋₆)cycloalkyl            optionally containing one ring oxygen atom, wherein ring^(C)            is optionally substituted with one R^(C), wherein R^(C) is            (C₁₋₄)alkyl or (C₁₋₄)fluoroalkyl; or        -   Ring^(D), wherein ring^(D) is a 5- to 6-membered heteroaryl            containing 1 to 3 heteroatoms independently selected from O,            N or S, wherein ring^(D) is unsubstituted or            mono-substituted with R^(D), wherein R^(D) is (C₁₋₄)alkyl or            (C₁₋₄)fluoroalkyl;

R⁶ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₁₋₄)fluoroalkyl; or    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one to three substituents        independently selected from halogen or (C₁₋₄)alkyl;

R⁷ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl; or    -   (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-; and

R⁸ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₂₋₄)fluoroalkyl;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one to three substituents        independently selected from halogen or (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy-C(O)—(C₁₋₄)alkylene-; or    -   (CH₃)₃Si—(CH₂)₂—O—(C₁)alkylene-;

wherein the characteristics disclosed in embodiments 2) to 38) above areintended to apply mutatis mutandis also to the compounds of formula(III) according to embodiment 42); wherein especially the followingembodiments are thus possible and intended and herewith speciallydisclosed in individualized form:

42+2, 42+4+2, 42+4, 42+5+2, 42+5, 42+9+2, 42+9+4+2, 42+9+4, 42+9+5+2,42+9+5, 42+9, 42+12+2, 42+12+4+2, 42+12+4, 42+12+5+2, 42+12+5, 42+12,42+13+2, 42+13+4+2, 42+13+4, 42+13+5+2, 42+13+5, 42+13, 42+15+2,42+15+4+2, 42+15+4, 42+15+5+2, 42+15+5, 42+15, 42+16+2, 42+16+4+2,42+16+4, 42+16+5+2, 42+16+5, 42+16, 42+19+2, 42+19+4+2, 42+19+4,42+19+5+2, 42+19+5, 42+19, 42+24+2, 42+24+4+2, 42+24+4, 42+24+5+2,42+24+5, 42+24+9+2, 42+24+9+4+2, 42+24+9+4, 42+24+9+5+2, 42+24+9+5,42+24+9, 42+24+12+2, 42+24+12+4+2, 42+24+12+4, 42+24+12+5+2, 42+24+12+5,42+24+12, 42+24+13+2, 42+24+13+4+2, 42+24+13+4, 42+24+13+5+2,42+24+13+5, 42+24+13, 42+24+15+2, 42+24+15+4+2, 42+24+15+4,42+24+15+5+2, 42+24+15+5, 42+24+15, 42+24+16+2, 42+24+16+4+2,42+24+16+4, 42+24+16+5+2, 42+24+16+5, 42+24+16, 42+24+19+2,42+24+19+4+2, 42+24+19+4, 42+24+19+5+2, 42+24+19+5, 42+24+19, 42+24;

In the list above, the numbers refer to the embodiments according totheir numbering provided hereinabove whereas “+” indicates thedependency from another embodiment. The different individualizedembodiments are separated by commas. In other words, “42+24+5” forexample refers to embodiment 42) depending on embodiment 24), dependingon embodiment 5), i.e. embodiment “42+24+5” corresponds to the compoundsof embodiment 42) further limited by the features of the embodiments 5)and 24).

43) Another embodiment relates to compounds of formula (III) accordingto embodiment 42), wherein

Y represents NR⁵; and X and Z independently represent N or CH (notably Yrepresents NR⁵; one of X and Z represents N, and the other of X and Zrepresents N or CH);

ring A represents an unsubstituted saturated 4- to 7-memberedmono-cyclic carbocyclic ring containing the ring nitrogen atom to whichR¹ is attached [for avoidance of doubt, said ring A is substituted withR¹ and carries no further substituent (i.e. R^(A) is absent)] [notablyring A represents pyrrolidin-1-3-diyl, or piperidin-1,4-diyl; especiallypiperidin-1,4-diyl];

R¹ represents phenyl, or 6-membered heteroaryl wherein said phenyl, or6-membered heteroaryl independently is mono-, di- or tri-substituted,wherein the substituents are independently selected from (C₁₋₄)alkyl;(C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy; halogen; cyano; or(C₃₋₆)cycloalkyl; [notably R¹ represents phenyl or pyridinyl, whichphenyl or pyridinyl independently is mono- or di-substituted wherein thesubstituents are independently selected from (C₁₋₄)alkyl (especiallymethyl); (C₁₋₄)alkoxy (especially methoxy); (C₁₋₃)fluoroalkyl(especially trifluoromethyl, or difluoromethyl); (C₁₋₃)fluoroalkoxy(especially trifluoromethoxy); halogen (especially fluoro or chloro);cyano; or (C₃₋₆)cycloalkyl (especially cyclopropyl)];

R² represents phenyl, or pyridinyl; wherein said phenyl or pyridinylindependently is mono-, or di-, or tri-substituted, wherein thesubstituents are independently selected from

-   -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkoxy;    -   (C₁₋₃)fluoroalkyl;    -   (C₁₋₃)fluoroalkoxy;    -   halogen; or    -   (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,        —O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl        optionally contains one ring oxygen atom;    -   [notably R² represents phenyl or pyridinyl, wherein said phenyl        or pyridinyl independently is mono- or di-substituted wherein        the substituents are independently selected from (C₁₋₄)alkyl;        (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        (C₁₋₃)fluoroalkoxy; halogen; (C₃₋₆)cycloalkyl;        (C₃₋₆)cycloalkyl-O—; and (C₃₋₆)cycloalkyl-CH₂—O—; in particular        R² represents phenyl, which is mono-substituted with        trifluoromethyl];

R³ represents hydrogen;

R⁵ represents

-   -   hydrogen;    -   (C₁₋₄)alkyl;    -   (C₁₋₄)alkyl which is mono-substituted with hydroxy,        (C₁₋₄)alkoxy, cyano;    -   (C₂₋₄)fluoroalkyl;    -   (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-;    -   (C₂₋₅)alkenyl;    -   (C₁₋₄)alkoxy-C(O)—(C₀₋₄)alkylene-;    -   (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is        optionally substituted by one or two substituents independently        selected from fluoro, (C₁₋₄)alkyl, nitro, or        (C₁₋₄)alkoxy-C(O)—NH—.    -   ring^(B)-X^(B)—; wherein X^(B) is a direct bond, or        (C₁₋₄)alkylene-; and wherein ring^(B) is a 4-membered saturated        heterocyclyl containing one ring heteratom selected from O and        NR^(B), wherein said ring^(B) is attached to X^(B) at a ring        carbon atom;    -   wherein said ring^(B) is optionally substituted by one        substituent selected from fluoro, (C₁₋₄)alkyl; and wherein R^(B)        independently represents        -   (C₁₋₄)alkoxy-C(O)—;        -   Ring^(D), wherein ring^(D) is a 5- to 6-membered heteroaryl            containing 1 to 3 heteroatoms independently selected from O,            N or S, wherein ring^(D) is unsubstituted or            mono-substituted with R^(D), wherein R^(D) is (C₁₋₄)alkyl or            (C₁₋₄)fluoroalkyl;    -   [notably R⁵ represents (C₁₋₄)alkyl (especially methyl);        (C₂₋₄)fluoroalkyl (especially 2,2-difluoro-propyl), or        (C₃₋₆)cycloalkyl (especially cyclopropyl)].

44) A further aspect of the invention relates to compounds of theformula (III) according to embodiment 42) or 43), which are alsocompounds of the formula (IV); wherein the absolute configuration is asdepicted in formula (IV):

Embodiment 44) further relates to the compounds of formula (I) accordingto any one of embodiments 1) to 39), wherein, in case R⁴ is differentfrom hydrogen, the absolute configuration is, mutatis mutandis, asdepicted in formula (IV).

45) Another embodiment relates to compounds according to embodiment 1)which are selected from the following compounds:

-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-4-(4-trifluoromethyl-pyridin-3-ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   [6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-5-oxo-4-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-2-yl]-acetic    acid methyl ester;-   2-Cyclopropyl-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-fluoro-2-methyl-propyl)-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-Cyclopropylmethyl-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(1-methyl-cyclopropylmethyl)-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-Ethyl-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-tert-Butyl-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-(1-Fluoro-cyclopropylmethyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-isopropyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-isopropenyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2-(2-trimethylsilanyl-ethoxymethyl)-2,4,6,7    tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-(2,2-Difluoro-propyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-2-(2-trimethylsilanyl-ethoxymethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-(2,2-Difluoro-propyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-(1-Fluoro-cyclopropylmethyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-Cyclopropyl-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-(2,2-Difluoro-propyl)-6-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-(1-Fluoro-cyclopropylmethyl)-6-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   2-Cyclopropyl-6-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   4-(2-Cyclopropyl-benzyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-isopropyl-benzyl)-2-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2-(2-trimethylsilanyl-ethoxymethyl)-2,4,5,7    tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-Ethoxymethyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-[²H₃]methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   [5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-acetic    acid methyl ester;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-hydroxy-ethyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Cyclopropoxy-benzyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-2-methyl-7-(3-trifluoromethyl-[6-²H]pyridine-2-yl-methyl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-d]pyrimidin-6-one;-   [5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-acetonitrile;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-hydroxy-2-methyl-propyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(2-Amino-ethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-2-methyl-propionic    acid methyl ester;-   2-(2,2-Diethoxy-ethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-acetamide;-   2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-N,N-dimethyl-acetamide;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-2-methyl-propionic    acid methyl ester;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-hydroxy-1,1-dimethyl-ethyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-hydroxy-propyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-[2-(3-methoxy-azetidin-1-yl)-ethyl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(6-Chloro-3-trifluoromethyl-pyridin-2-ylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(6-fluoro-3-trifluoromethyl-pyridin-2-ylmethyl)-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-7-(6-methyl-3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(6-methoxy-3-trifluoromethyl-pyridin-2-ylmethyl)-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(3-hydroxy-2-methyl-propyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(2,3-Dihydroxy-propyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-((R)-2-hydroxy-3-methoxy-propyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-Chloro-3-[5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-propionic    acid methyl ester;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-2-methyl-propionitrile;-   2-(3-Amino-2-methyl-propyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-((S)-2-hydroxy-3-methoxy-propyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2,6-Dimethyl-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Methoxy-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   3-Fluoro-2-{4-[2-methyl-6-oxo-7-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-5-yl]-piperidin-1-yl}-benzonitrile;-   7-(6-Dimethylamino-3-trifluoromethyl-pyridin-2-ylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-7-(6-methylamino-3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-(2′-Fluoro-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-Dimethylamino-3-[5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-propionic    acid methyl ester;-   5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(2-Dimethylamino-3-hydroxy-propyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-methylamino-ethyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(2-Dimethylamino-ethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-fluoro-6-trifluoromethyl-benzyl)-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-pyrrolidin-1-yl-ethyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-piperidin-1-yl-ethyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-morpholin-4-yl-ethyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-[2-(4-methyl-piperazin-1-yl)-ethyl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   N-{2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-ethyl}-acetamide;-   {2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,    d]pyrimidin-2-yl]-ethyl}-carbamic acid tert-butyl ester;-   2-Methyl-5-(3′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(2-Cyclopropylamino-ethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-[2-(isopropyl-methyl-amino)-ethyl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-[2-(Cyclopropyl-methyl-amino)-ethyl]-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-{2-[(2-methoxy-ethyl)-methyl-amino]-ethyl}-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-propionamide;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-oxetan-3-yl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-propionitrile;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-nitro-cyclohexyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   {2,2,2-Trifluoro-1-[5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-1-methyl-ethyl}-carbamic    acid tert-butyl ester;-   2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-isobutyramide;-   4′-Methyl-4-[2-methyl-6-oxo-7-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-5-yl]-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-carbonitrile;-   5-(4′-Fluoro-2′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-2-methyl-propionitrile;-   2-(2-Amino-1,1-dimethyl-ethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-azetidine-1-carboxylic    acid tert-butyl ester;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-pyrrolidine-1-carboxylic    acid tert-butyl ester;-   5-(2′,4′-Dimethoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester;-   {2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-cyclopentyl}-carbamic    acid tert-butyl ester;-   4-Chloro-N-{2-[5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-1,1-dimethyl-ethyl}-benzenesulfonamide;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(1-isobutyl-azetidin-3-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-[1-(2,2-Difluoro-ethyl)-azetidin-3-yl]-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-[1-(2-Fluoro-ethyl)-azetidin-3-yl]-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-4,4-Difluoro-2-[5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester;-   (S)-4,4-Difluoro-2-[5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester;-   N-{2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-1,1-dimethyl-ethyl}-2-nitro-benzenesulfonamide;-   2-((R)-4,4-Difluoro-pyrrolidin-2-ylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-((S)-4,4-Difluoro-pyrrolidin-2-ylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(1-Acetyl-pyrrolidin-3-yl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(1-Acetyl-azetidin-2-ylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(1-Acetyl-pyrrolidin-2-ylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-azetidine-1-carboxylic    acid methyl ester;-   (S)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-azetidine-1-carboxylic    acid tert-butyl ester;-   (S)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-azetidine-1-carboxylic    acid methyl ester;-   (S)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-azetidine-1-carboxylic    acid ethyl ester;-   (S)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-azetidine-1-carboxylic    acid isopropyl ester;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-azetidine-1-carboxylic    acid ethyl ester;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-azetidine-1-carboxylic    acid isopropyl ester;-   (R)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-azetidine-1-carboxylic    acid tert-butyl ester;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(1-isobutyryl-azetidin-3-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-azetidine-1-carboxylic    acid isobutyl ester;-   (R)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-azetidine-1-carboxylic    acid methyl ester;-   (R)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-azetidine-1-carboxylic    acid ethyl ester;-   (R)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-ylmethyl]-azetidine-1-carboxylic    acid isopropyl ester;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(1-methanesulfonyl-azetidin-3-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-azetidine-1-sulfonic    acid dimethylamide;-   5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-azetidine-1-carboxylic    acid oxetan-3-yl ester;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-azetidine-1-carboxylic    acid 3-trifluoromethyl-oxetan-3-yl ester;-   3-[5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-azetidine-1-carboxylic    acid 3-methyl-oxetan-3-yl ester;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-[1-(5-methyl-[1,3,4]oxadiazol-2-yl)-azetidin-3-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-[1-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-azetidin-3-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2-[1-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-azetidin-3-yl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-2-carboxylic    acid isopropyl ester;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-2-carboxylic    acid dimethylamide;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-methyl-propenyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-methyl-allyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-isobutyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-[2-([²H₃]methyl)[1,1,2,3,3,3-²H₆]propyl]-7-(2-trifluoromethyl-benzyl)-    2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-oxo-azetidin-3-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(1-methyl-cyclopropylmethyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(2,2-Difluoro-ethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(1,1-Dimethyl-prop-2-ynyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-isopropyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-([1,1,1,2,3,3,3-²H₇]propan-2-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-([1,1,1,3,3,3-²H₆]propan-2-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(3-fluoro-oxetan-3-ylmethyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-Cyclopropylmethyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(3-methyl-oxetan-3-ylmethyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(1-Fluoro-cyclopropylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(2-fluoro-2-methyl-propyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-Ethyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-[1,1,2,2,2-²H₅]Ethyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-(3-hydroxy-oxetan-3-ylmethyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(2,2-Difluoro-propyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-tert-Butyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-Cyclopropyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-((S)-2-fluoro-propyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-((R)-2-fluoro-propyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-((S)-2,2-Difluoro-1-methyl-ethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-((R)-2,2-Difluoro-1-methyl-ethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-((R)-2,2-Difluoro-cyclopropylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-((S)-2,2-Difluoro-cyclopropylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(2,2-Difluoro-propyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2-trifluoromethyl-benzyl)-2-(2-trimethylsilanyl-ethoxymethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(1-Fluoro-cyclopropylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(1-Fluoro-cyclopropylmethyl)-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-(2,2-Difluoro-propyl)-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-Cyclopropyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-Cyclopropyl-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Bromo-6-trifluoromethyl-benzyl)-2-cyclopropyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Bromo-6-trifluoromethyl-benzyl)-2-(2,2-difluoro-propyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-4-methyl-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[(S)-1-(2-Fluoro-6-methyl-phenyl)-azepan-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[(R)-1-(2-Fluoro-6-methyl-phenyl)-azepan-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-Methoxymethyl-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Cyclopropyl-benzyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-isopropyl-benzyl)-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethoxy-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Chloro-benzyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(4-Chloro-2,5-dimethyl-2H-pyrazol-3-yl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-trifluoromethyl-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-trifluoromethoxy-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Chloro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-7-[(R)-1-(2-trifluoromethyl-phenyl)-ethyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-7-[(S)-1-(2-trifluoromethyl-phenyl)-ethyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Cyclopropylmethoxy-benzyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(4-isopropyl-pyrimidin-5-ylmethyl)-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-7-[2-(oxetan-3-yloxy)-benzyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-isopropoxy-benzyl)-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Ethoxy-benzyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Isopropyl-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Cyclopropyl-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(4-isopropoxy-pyridazin-3-ylmethyl)-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-pyrrolidin-3-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[(R)-1-(2-Fluoro-6-methyl-phenyl)-pyrrolidin-3-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[(R)-1-(2,6-Dimethyl-phenyl)-pyrrolidin-3-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[(S)-1-(2,6-Dimethyl-phenyl)-pyrrolidin-3-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[(R)-1-(2-Fluoro-6-methyl-phenyl)-3-methyl-pyrrolidin-3-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[(S)-1-(2-Fluoro-6-methyl-phenyl)-3-methyl-pyrrolidin-3-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[(R)-1-(2-Fluoro-6-methyl-phenyl)-piperidin-3-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-azetidin-3-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5-one;-   6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5-one;    and-   6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5-one.

46) In addition to the compounds listed in embodiment 45), furthercompounds according to embodiment 1) are selected from the followingcompounds:

-   (S)-6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,7-dimethyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-2-(2,2-Difluoro-propyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-2-(2,2-Difluoro-propyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-2-Cyclopropyl-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-2-Cyclopropyl-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one.

47) In addition to the compounds listed in embodiments 45) and 46),further compounds according to embodiment 1) are selected from thefollowing compounds:

-   1-Cyclopropylmethyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   1-Cyclopropyl-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   1-Cyclopropylmethyl-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-1-(1-methyl-cyclopropylmethyl)-4-(2-trifluoromethyl-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-1-(2-fluoro-2-methyl-propyl)-4-(2-trifluoromethyl-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   1-(2,2-Difluoro-propyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-1-(2,2-Difluoro-propyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-(2-trifluoromethyl-benzyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;    and-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one.

48) In addition to the compounds listed in embodiments 45) to 47),further compounds according to embodiment 1) are selected from thefollowing compounds:

-   1-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-3-(2-trifluoromethyl-benzyl)-1,3,6,7-tetrahydro-purin-2-one;-   1-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-3-(2-trifluoromethyl-benzyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,3,6,7-tetrahydro-purin-2-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-4-(2-trifluoromethyl-benzyl)-6,7-dihydro-4H-oxazolo[5,4-d]pyrimidin-5-one;    and-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2-methyl-4-(2-trifluoromethyl-benzyl)-6,7-dihydro-4H-thiazolo[5,4-d]pyrimidin-5-one.-   49) In addition to the compounds listed in embodiments 45) to 48),    further compounds according to embodiment 1) are selected from the    following compounds:-   6-[1-(2-Fluoro-6-trifluoromethoxy-phenyl)-piperidin-4-yl]-2-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-trifluoromethyl-phenyl)-piperidin-4-yl]-2-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2,6-Difluoro-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Cyclopropyl-benzyl)-5-[1-(2-fluoro-6-trifluoromethyl-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Cyclopropyl-benzyl)-5-[1-(2-fluoro-6-trifluoromethoxy-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   2-{4-[7-(2-Cyclopropyl-benzyl)-2-methyl-6-oxo-2,4,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-5-yl]-pi-peridin-1-yl}3-fluoro-benzonitrile;-   7-(2-Cyclopropyl-benzyl)-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7-(2-cyclopropyl-benzyl)-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Cyclopropyl-benzyl)-5-[1-(2,6-difluoro-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-7-[(R)-1-(2-trifluoromethyl-phenyl)-ethyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-7-[(S)-1-(2-trifluoromethyl-phenyl)-ethyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   3-Fluoro-2-(4-{2-methyl-6-oxo-7-[(R)-1-(2-trifluoromethyl-phenyl)-ethyl]-2,4,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-5-yl}-piperidin-1-yl)-benzonitrile;-   3-Fluoro-2-(4-{2-methyl-6-oxo-7-[(S)-1-(2-trifluoromethyl-phenyl)-ethyl]-2,4,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-5-yl}-piperidin-1-yl)-benzonitrile;-   5-[1-(2,6-Difluoro-phenyl)-piperidin-4-yl]-2-methyl-7-[(S)-1-(2-trifluoromethyl-phenyl)-ethyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   6-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-2-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-2-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   5-[1-(2-Cyclopropyl-6-fluoro-phenyl)-piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   6-[1-(2-Cyclopropyl-6-fluoro-phenyl)-piperidin-4-yl]-2-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   7-(2-Cyclopropyl-benzyl)-5-[1-(2-cyclopropyl-6-fluoro-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Cyclopropyl-benzyl)-5-[1-(2-difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one.

50) In addition to the compounds listed in embodiments 45) to 49),further compounds according to embodiment 1) are selected from thefollowing compounds:

-   4-(2-Cyclopropyl-benzyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-2-(tetrahydro-pyran-2-yl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   4-(2-Cyclopropyl-benzyl)-6-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl-2-(tetrahydro-pyran-2-yl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-4-(2-Cyclopropyl-benzyl)-6-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-4-(2-Cyclopropyl-benzyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-4-(2-Cyclopropyl-benzyl)-2-(2,2-difluoro-propyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-4-(2-Cyclopropyl-benzyl)-2-(2,2-difluoro-propyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-2-Cyclopropyl-4-(2-cyclopropyl-benzyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-2-Cyclopropyl-4-(2-cyclopropyl-benzyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-2-Cyclopropyl-4-(2-cyclopropyl-benzyl)-6-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-2-Cyclopropyl-4-(2-cyclopropyl-benzyl)-6-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl-2-(tetrahydro-pyran-2-yl)-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-2-Cyclopropyl-6-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-2-Cyclopropyl-6-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,7-dimethyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-2-(2,2-Difluoro-propyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-2-(2,2-Difluoro-propyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-2-Cyclopropyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-2-Cyclopropyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-2-Cyclopropyl-5-[1-(2-difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-2-Cyclopropyl-5-[1-(2-difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-methyl-2-(tetrahydro-pyran-2-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-7-(2-Cyclopropyl-benzyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-7-(2-Cyclopropyl-benzyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7-(2-cyclopropyl-benzyl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7-(2-cyclopropyl-benzyl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-7-(2-Cyclopropyl-benzyl)-5-[1-(2-difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-7-(2-Cyclopropyl-benzyl)-5-[1-(2-difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-7-(2-Cyclopropyl-benzyl)-5-[1-(2-cyclopropyl-6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-7-(2-Cyclopropyl-benzyl)-5-[1-(2-cyclopropyl-6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-6-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-2-cyclopropyl-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-6-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-2-cyclopropyl-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-2-Cyclopropyl-6-[1-(2-difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (S)-2-Cyclopropyl-6-[1-(2-difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one;-   (R)-5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Cyclopropyl-6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Cyclopropyl-6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-2-cyclopropyl-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-2-cyclopropyl-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-2-cyclopropyl-7-(2-cyclopropyl-benzyl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-2-cyclopropyl-7-(2-cyclopropyl-benzyl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-2-Cyclopropyl-7-(2-cyclopropyl-benzyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-2-Cyclopropyl-7-(2-cyclopropyl-benzyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-2-(tetrahydro-pyran-2-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-2-(tetrahydro-pyran-2-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-(4′-Difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2-(tetrahydro-pyran-2-yl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-2-Cyclopropyl-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-2-Cyclopropyl-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-(4′-Difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-(4′-Difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-(4′-Difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-(4′-Difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-2-Cyclopropyl-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-2-Cyclopropyl-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Bromo-6-fluoro-phenyl)-piperidin-4-yl]-2-cyclopropyl-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Bromo-6-fluoro-phenyl)-piperidin-4-yl]-2-cyclopropyl-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-(2′-Methoxy-4′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-(2′-Methoxy-4′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   7-(2-Cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2-(tetrahydro-pyran-2-yl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7-(2-cyclopropyl-benzyl)-4-methyl-2-(tetrahydro-pyran-2-yl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-7-(2-Cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-7-(2-Cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-7-(2-Cyclopropyl-benzyl)-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-7-(2-Cyclopropyl-benzyl)-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-7-(2-Cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-7-(2-Cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7-(2-cyclopropyl-benzyl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7-(2-cyclopropyl-benzyl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-7-(2-Cyclopropyl-benzyl)-5-(2′-methoxy-4′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-7-(2-Cyclopropyl-benzyl)-5-(2′-methoxy-4′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-(4′-Chloro-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-(4′-Chloro-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-(4′-Chloro-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2-cyclopropyl-benzyl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-(4′-Chloro-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2-cyclopropyl-benzyl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-2-Cyclopropyl-7-(2-cyclopropyl-benzyl)-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-2-Cyclopropyl-7-(2-cyclopropyl-benzyl)-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-2-Cyclopropyl-7-(2-cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-2-Cyclopropyl-7-(2-cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (R)-5-[1-(2-Bromo-6-fluoro-phenyl)-piperidin-4-yl]-7-(2-cyclopropyl-benzyl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one;-   (S)-5-[1-(2-Bromo-6-fluoro-phenyl)-piperidin-4-yl]-7-(2-cyclopropyl-benzyl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one.

The compounds of formula (I) according to embodiments 1) to 50) andtheir pharmaceutically acceptable salts can be used as medicaments, e.g.in the form of pharmaceutical compositions for enteral (such especiallyoral) or parenteral administration (including topical application orinhalation).

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Remington, The Science and Practice of Pharmacy, 21st Edition(2005), Part 5, “Pharmaceutical Manufacturing” [published by LippincottWilliams & Wilkins]) by bringing the described compounds of formula (I)or (II), or their pharmaceutically acceptable salts, optionally incombination with other therapeutically valuable substances, into agalenical administration form together with suitable, non-toxic, inert,therapeutically compatible solid or liquid carrier materials and, ifdesired, usual pharmaceutical adjuvants.

The present invention also relates to a method for the prevention ortreatment of a disease or disorder mentioned herein comprisingadministering to a subject a pharmaceutically active amount of acompound of formula (I) as defined in any one of embodiments 1) to 50).

In a preferred embodiment of the invention, the administered amount iscomprised between 1 mg and 1000 mg per day, particularly between 5 mgand 500 mg per day, more particularly between 25 mg and 400 mg per day,especially between 50 mg and 200 mg per day.

Whenever the word “between” is used to describe a numerical range, it isto be understood that the end points of the indicated range areexplicitly included in the range. For example: if a temperature range isdescribed to be between 40° C. and 80° C., this means that the endpoints 40° C. and 80° C. are included in the range; or if a variable isdefined as being an integer between 1 and 4, this means that thevariable is the integer 1, 2, 3, or 4.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X. In theparticular case of temperatures, the term “about” placed before atemperature “Y” refers in the current application to an intervalextending from the temperature Y minus 10° C. to Y plus 10° C., andpreferably to an interval extending from Y minus 5° C. to Y plus 5° C.

For avoidance of any doubt, if compounds are described as useful for theprevention or treatment of certain diseases, such compounds are likewisesuitable for use in the preparation of a medicament for the preventionor treatment of said diseases.

The compounds of formula (I) as defined in any one of embodiments 1) to50) are useful for the prevention/prophylaxis or treatment of diseasesand disorders related to pathogenic events associated with elevatedlevels of C5a and/or with C5aR activation.

Such diseases and disorders related to pathogenic events associated withelevated levels of C5a and/or with C5aR activation are especially:

-   -   vasculitic diseases or disorders,    -   inflammatory diseases or disorders involving intravascular        microvesicle release,    -   immune complex (IC) diseases or disorders,    -   neurodegenerative diseases or disorders,    -   complement related inflammatory diseases or disorders,    -   bullous diseases or disorders,    -   diseases or disorders related to ischemia and/or ischemic        reperfusion injury,    -   inflammatory bowel diseases or disorders,    -   autoimmune diseases or disorders, or, in addition to the above        listed,    -   cancer.

In addition to the above-listed diseases and disorders, further diseasesand disorders related to pathogenic events associated with elevatedlevels of C5a and/or with C5aR activation are:

-   -   further inflammatory diseases or disorders associated with        elevated levels of C5a and/or with C5aR activation such as        especially neutropenia, sepsis, septic shock, stroke,        inflammation associated with severe burns, osteoarthritis, acute        (adult) respiratory distress syndrome (ARDS), chronic pulmonary        obstructive disorder (COPD), asthma (especially bronchial        asthma), systemic inflammatory response syndrome (SIRS), tissue        graft rejection, hyperacute rejection of transplanted organs,        multiple organ dysfunction syndrome (MODS), diabetic        retinopathy, neuromyelitis optica, and glomerulonephritis        including Heyman nephritis/membranous glomerulonephritis,        Berger's disease (IgA nephropathy), and other forms of        glomerulonephritis such as C3 glomerulopathy including dense        deposit disease;

as well as

-   -   hemotological diseases which are associated with activation of        coagulation and fibrinolytic systems, disseminated intravascular        coagulation (DIC), pernicious anemia, warm and cold autoimmune        hemolytic anemia (AIHA), anti-phospholipid syndrome and its        associated complications, arterial or venous thrombosis,        pregnancy complications such as recurrent miscarriage and fetal        death, preeclampsia, placental insufficiency, fetal growth        restriction, cervical remodeling and preterm birth, idiopathic        thrombocytopenic purpura (ITP), atypical hemolytic uremic        syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH),        allergic transfusion reactions, acute antibody-mediated kidney        allograft rejection, cold agglutinin disease and glaucoma.

The present compounds may in addition be useful for

-   -   the prevention or treatment of deleterious consequences of        contact sensitivity and inflammation caused by contact with        artificial surfaces;    -   the prevention or treatment of increased leukocyte and platelet        activation (and infiltration to tissues thereof);    -   the prevention or treatment of pathologic sequelae (such as        especially prevention or treatment of the development of tissue        injury, especially of pulmonary tissue injury) associated to an        intoxication or an injury such as a trauma, an hemorrhage, a        shock, or surgery including transplantation, including multiple        organ failure (MOF), septic shock, shock due to intoxication        (such as shock due to snake venom), or acute lung inflammatory        injury;    -   the prevention or treatment of pathologic sequelae associated        with insulin-dependent diabetes mellitus;    -   the prevention of/the reduction of the risk of myocardial        infarction or thrombosis; prevention or treatment of edema or        increased capillary permeability;    -   the prevention of/the reduction of coronary endothelial        dysfunction induced by cardiopulmonary bypass and/or        cardioplegia.

Vasculitic diseases or disorders include especially vasculitis, ANCAassociated vasculitis and glomerulonephritis (GN, especially rapidlyprogressive GN) associated with ANCA associated vasculitis, leukoclasticvasculitis, granulomatosis with polyangiitis (GPA, also referred to asWegener's granulomatosis), microscopic polyangiitis, Churg-Strausssyndrome, Henoch-Schönlein purpura, polyateritis nodosa,cryoglobulinaemia, giant cell arteritis (GCA), Behcet's disease, andTakayasu's arteritis (TAK).

Inflammatory diseases or disorders involving intravascular microvesiclerelease include especially thrombotic microangiopathy, and sickle celldisease.

Immune complex (IC) diseases or disorders include especiallycryoglobulinemia, Sjögren's syndrome (and associated immunologicalprofiles), Goodpasture syndrome (antiglomerular basement antibodydisease) and glomerulonephritis (GN, especially rapidly progressive GN)or pulmonary hemorrhage associated with Goodpasture syndrome, andhypersensitivity;

Neurodegenerative diseases and disorders include especially amyotrophiclateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease,Huntington's disease, Guillain-Barre syndrome, neuropathy, and cognitivefunction decline associated with cardiopulmonary bypass surgery andrelated procedures.

Complement related inflammatory diseases or disorders include especiallycoronary thrombosis, vascular occlusion, post-surgical vascularreocclusion, atherosclerosis, traumatic central nervous system injury,arrhythmogenic cardiomyopathy, bronchoconstriction, acute respiratorydistress syndrome (ARDS), Chronic Obstructive Pulmonary Disorder (COPD),complement mediated thrombotic microangiopathies including atypicalhaemolytic uremic syndrome, and Gaucher disease.

Bullous diseases or disorders include especially bullous pemphigoid,bullous acquisita, Pemphigus foliaceus, Pemphigus vulgaris,sub-epidermal blisters, and hidradenitis suppurativa.

Diseases or disorders related to ischemia and/or ischemic reperfusioninjury include especially ischemic reperfusion injury (includingmyocardial ischemia-reperfusion injury, and ischemic/reperfusion injuryresulting from transplantation, including solid organ transplant),ischemic colitis, and cardiac ischemia.

Inflammatory bowel diseases or disorders include especially irritablebowel syndrome, ulcerative colitis, Crohn's disease, and inflammatorybowel disease (IBD).

Autoimmune diseases or disorders include especially rheumatoidarthritis, osteoarthritis, systemic lupus erythematosus (SLE) andglomerulonephritis (GN, especially rapidly progressive GN) associatedwith lupus erythematosus (lupus nephritis), central nervous system (CNS)lupus, dermatomyositis, Pemphigus, systemic sclerosis (scleroderma),autoimmune hemolytic and thrombocytopenic states, immunovasculitis,mixed cryoglobulinemia, atopic dermatitis, chronic urticaria, psoriasis,myasthenia gravis, and anti-phospholipid syndrome.

Further inflammatory diseases or disorders associated with elevatedlevels of C5a and/or with C5aR activation include especiallyneutropenia, sepsis, septic shock, stroke, inflammation associated withsevere burns, osteoarthritis, acute (adult) respiratory distresssyndrome (ARDS), chronic pulmonary obstructive disorder (COPD), asthma,especially bronchial asthma, systemic inflammatory response syndrome(SIRS), tissue graft rejection, hyperacute rejection of transplantedorgans, multiple organ dysfunction syndrome (MODS), diabeticretinopathy, neuromyelitis optica, and glomerulonephritis includingHeyman nephritis/membranous glomerulonephritis, Berger's disease (IgAnephropathy), and other forms of glomerulonephritis such as C3glomerulopathy including dense deposit disease.

The term “cancer” notably refers to skin cancer including melanomaincluding metastatic melanoma; lung cancer including non-small cell lungcancer; bladder cancer including urinary bladder cancer, urothelial cellcarcinoma; renal carcinomas including renal cell carcinoma, metastaticrenal cell carcinoma, metastatic renal clear cell carcinoma;gastro-intestinal cancers including colorectal cancer, metastaticcolorectal cancer, familial adenomatous polyposis (FAP), oesophagealcancer, gastric cancer, gallbladder cancer, cholangiocarcinoma,hepatocellular carcinoma, and pancreatic cancer such as pancreaticadenocarcinoma or pancreatic ductal carcinoma; endometrial cancer;ovarian cancer; cervical cancer; neuroblastoma; prostate cancerincluding castrate-resistant prostate cancer; brain tumors includingbrain metastases, malignant gliomas, glioblastoma multiforme,medulloblastoma, meningiomas; breast cancer including triple negativebreast carcinoma; oral tumors; nasopharyngeal tumors; thoracic cancer;head and neck cancer; leukemias including acute myeloid leukemia, adultT-cell leukemia; carcinomas; adenocarcinomas; thyroid carcinomaincluding papillary thyroid carcinoma; choriocarcinoma; Ewing's sarcoma;osteosarcoma; rhabdomyosarcoma; Kaposi's sarcoma; lymphoma includingBurkitt's lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiplemyelomas; or virally induced tumors.

When used for the prevention/prophylaxis or treatment of a cancer, suchuse includes use of the present compounds as single therapeutic agentsand their use in combination with one or more chemotherapy agents and/orradiotherapy and/or targeted therapy (especially in combination withtargeted therapy).

The terms “radiotherapy” or “radiation therapy” or “radiation oncology”,refer to the medical use of ionizing radiation in theprevention/prophylaxis (adjuvant therapy) and/or treatment of cancer;including external and internal radiotherapy.

The term “targeted therapy” refers to the prevention/prophylaxis(adjuvant therapy) and/or treatment of cancer with one or moreanti-neoplastic agents such as small molecules or antibodies which acton specific types of cancer cells or stromal cells. Some targetedtherapies block the action of certain enzymes, proteins, or othermolecules involved in the growth and spread of cancer cells. Other typesof targeted therapies help the immune system kill cancer cells(immunotherapies); or inhibit angiogenesis, the growth and formation ofnew blood vessels in the tumor; or deliver toxic substances directly tocancer cells and kill them. An example of a targeted therapy which is inparticular suitable to be combined with the compounds of the presentinvention is immunotherapy, especially immunotherapy targeting theprogrammed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1.

When used in combination with the present compounds, the term “targetedtherapy” especially refers to agents such as:

-   -   a) Epidermal growth factor receptor (EGFR) inhibitors or        blocking antibodies (for example Gefitinib, Erlotinib, Afatinib,        Icotinib, Lapatinib, Panitumumab, Zalutumumab, Nimotuzumab,        Matuzumab and Cetuximab);    -   b) RAS/RAF/MEK pathway inhibitors (for example Vemurafenib,        Sorafenib, Dabrafenib, GDC-0879, PLX-4720, LGX818, RG7304,        Trametinib (GSK1120212), Cobimetinib (GDC-0973/XL518),        Binimetinib (MEK162, ARRY-162), Selumetinib (AZD6244));    -   c) Aromatase inhibitors (for example Exemestane, Letrozole,        Anastrozole, Vorozole, Formestane, Fadrozole);    -   d) Angiogenesis inhibitors, especially VEGF signalling        inhibitors such as Bevacuzimab (Avastin), Ramucirumab, Sorafenib        or Axitinib;    -   e) Immune Checkpoint inhibitors (for example: anti-PD1        antibodies such as Pembrolizumab (Lambrolizumab, MK-3475),        Nivolumab, Pidilizumab (CT-011), AMP-514/MED10680, PDR001,        SHR-1210; REGN2810, BGBA317; fusion proteins targeting PD-1 such        as AMP-224; small molecule anti-PD1 agents such as for example        compounds disclosed in WO2015/033299, WO2015/044900 and        WO2015/034820; anti-PD1L antibodies, such as BMS-936559,        atezolizumab (MPDL3280A, RG7446), MEDI4736, avelumab        (MSB0010718C), durvalumab (MEDI4736); anti-PDL2 antibodies, such        as AMP224; anti-CTLA-4 antibodies, such as ipilimumab,        tremilmumab; anti-Lymphocyte-activation gene 3 (LAG-3)        antibodies, such as BMS-986016, IMP701, MK-4280, ImmuFact        IMP321; anti T cell immunoglobulin mucin-3 (TIM-3) antibodies,        such as MBG453; anti-CD137/4-1BB antibodies, such as        BMS-663513/urelumab, PF-05082566; anti T cell immunoreceptor        with Ig and ITIM domains (TIGIT) antibodies, such as RG6058        (anti-TIGIT, MTIG7192A);    -   f) Vaccination approaches (for example dendritic cell        vaccination, peptide or protein vaccination (for example with        gp100 peptide or MAGE-A3 peptide);    -   g) Re-introduction of patient derived or allogenic (non-self)        cancer cells genetically modified to secrete immunomodulatory        factors such as granulocyte monocyte colony stimulating factor        (GMCSF) gene-transfected tumor cell vaccine (GVAX) or        Fms-related tyrosine kinase 3 (Flt-3) ligand gene-transfected        tumor cell vaccine (FVAX), or Toll like receptor enhanced GM-CSF        tumor based vaccine (TEGVAX);    -   h) T-cell based adoptive immunotherapies, including chimeric        antigen receptor (CAR) engineered T-cells (for example CTL019);    -   i) Cytokine or immunocytokine based therapy (for example        Interferon alpha, interferon beta, interferon gamma, interleukin        2, interleukin 15);    -   j) Toll-like receptor (TLR) agonists (for example resiquimod,        imiquimod, glucopyranosyl lipid A, CpG oligodesoxynucleotides);    -   k) Thalidomide analogues (for example Lenalidomide,        Pomalidomide);    -   l) Indoleamin-2,3-Dioxgenase (IDO) and/or        Tryptophane-2,3-Dioxygenase (TDO) inhibitors (for example        RG6078/NLG919/GDC-0919; Indoximod/1MT (1-methyltryptophan),        INCB024360/Epacadostat, PF-06840003 (EOS200271), F001287);    -   m) Activators of T-cell co-stimulatory receptors (for example        anti-OX40/CD134 (Tumor necrosis factor receptor superfamily,        member 4, such as RG7888 (MOXR0916), 9B12; MED16469, GSK3174998,        MED10562), anti OX40-Ligand/CD252; anti-glucocorticoid-induced        TNFR family related gene (GITR) (such as TRX518, MED11873,        MK-4166, BMS-986156), anti-CD40 (TNF receptor superfamily        member 5) antibodies (such as Dacetuzumab (SGN-40), HCD122,        CP-870,893, RG7876, ADC-1013, APX005M, SEA-CD40);        anti-CD40-Ligand antibodies (such as BG9588); anti-CD27        antibodies such as Varlilumab);    -   n) Molecules binding a tumor specific antigen as well as a        T-cell surface marker such as bispecific antibodies (for example        RG7802 targeting CEA and CD3) or antibody fragments, antibody        mimetic proteins such as designed ankyrin repeat proteins        (DARPINS), bispecific T-cell engager (BITE, for example AMG103,        AMG330);    -   o) Antibodies or small molecular weight inhibitors targeting        colony-stimulating factor-1 receptor (CSF-1R) (for example        Emactuzumab (RG7155), Cabiralizumab (FPA-008), PLX3397);    -   p) Agents targeting immune cell check points on natural killer        cells such as antibodies against Killer-cell immunoglobulin-like        receptors (KIR) for example Lirilumab (IPH2102/BMS-986015);    -   q) Agents targeting the Adenosine receptors or the ectonucleases        CD39 and CD73 that convert ATP to Adenosine, such as MED19447        (anti-CD73 antibody), PBF-509; CPI-444 (Adenosine A2a receptor        antagonist).

When used in combination with the present compounds, immune checkpointinhibitors, and especially those targeting the PD-1 receptor or itsligand PD-L1, are preferred.

The invention further relates to a method of modulating (especiallydownregulating) the consequences of the complement activation(especially by activating innate cells) in a subject in need thereof[especially in a subject having a disease or disorder related topathogenic events associated with elevated levels of C5a and/or withC5aR activation; in particular in a subject having a vasculitic diseaseor disorder, an inflammatory disease or disorder involving intravascularmicrovesicle release, an immune complex (IC) disease or disorder, aneurodegenerative disease or disorder, a complement related inflammatorydisease or disorder, a bullous disease or disorder, a disease ordisorder related to ischemia and/or ischemic reperfusion injury, aninflammatory bowel disease or disorder, or an autoimmune disease ordisorder; or in a subject having a contact sensitivity or aninflammation caused by contact with artificial surfaces; an increasedleukocyte and platelet activation (and infiltration to tissues thereof);a pathologic sequelae associated to an intoxication or an injury such asa trauma, an hemorrhage, a shock, or surgery including transplantation,including multiple organ failure (MOF), septic shock, shock due tointoxication (such as shock due to snake venom), or acute lunginflammatory injury; a pathologic sequelae associated withinsulin-dependent diabetes mellitus; a myocardial infarction orthrombosis; an edema or an increased capillary permeability; or areduction of coronary endothelial dysfunction induced by cardiopulmonarybypass and/or cardioplegia], comprising administering to said subject apharmaceutically active amount of a compound of formula (I) as definedin any one of embodiments 1) to 50). For avoidance of doubt, the term“modulating the complement activation” is to be understood asdownregulating/reducing the amplification of the immune response anddownregulating/reducing the activation of the cell-killing membraneattack complex, especially by activating innate cells.

PREPARATION OF COMPOUNDS OF FORMULA (1)

A further aspect of the invention is a process for the preparation ofcompounds of Formula (I) as defined in any one of embodiments 1) to 50).Compounds of Formula (I) can be prepared from commercially available orwell known starting materials according to the methods described in theexperimental part, by analogous methods; or according to the generalsequence of reactions outlined below, wherein R¹, R^(A), R², R³, R⁴, X,Y and Z are as defined for Formula (1).

Other abbreviations used herein are explicitly defined or are as definedin the experimental section. In some instances, the generic groups R¹,R^(A), R², R³, R⁴, X, Y and Z might be incompatible with the assemblyillustrated in the schemes below and so will require the use ofprotecting groups (PG). The use of protecting groups is well known inthe art (see for example “Protective Groups in Organic Synthesis”, T. W.Greene, P. G. M. Wuts, Wiley-Interscience, 1999). For the purposes ofthis discussion, it will be assumed that such protecting groups asnecessary are in place. The compounds obtained may also be convertedinto salts, especially pharmaceutically acceptable salts thereof in amanner known per se.

Compounds of structure Ia which are compounds of Formula (I) wherein R⁴represents hydrogen, can be prepared according to the synthetic routesgiven in scheme A1 below (wherein ring A may in addition be optionallysubstituted with R^(A) as explicitly defined).

Compounds of structure A-1 can be prepared by reductive amination ofsuitable aldehydes of structure BB-4 with suitable amines of structureBB-7 using standard conditions such as treatment with NaBH(OAc)₃ in theoptional presence of AcOH and a suitable solvent such as DCM, MeOH, THFor a mixture thereof at temperatures around RT.

Alternatively, NaBH₄ can be used as reducing agent in the presence ofTFE as solvent according to Synthesis, 2011, 3, 490-496. Optionally, atwo-step procedure can be applied (i) condensation of a suitablealdehyde of structure BB-4 with amines of structure BB-7 in the presenceof a suitable solvent such as MeOH at temperatures around 60° C. and(ii) subsequent reduction of the intermediate imine by treatment withNaBH₄ at temperatures between 0° C. and RT (Scheme A1, step a).

Diamino compounds of structure A-2 can be prepared by reduction of thenitro group in compounds of structure A-1 using standard conditions suchas catalytic hydrogenation with a suitable catalyst such as Pd/C in asuitable solvent such as EtOAc or EtOH or a mixture thereof (Scheme A1,step b).

Alternatively, diamino compounds of structure A-2 can be prepared byreductive alkylation of a suitable amine of structure BB-5 with ketonesof structure BB-8 using standard conditions such as treatment withNaBH(OAc)₃ in the optional presence of AcOH and a suitable solvent suchas DCM, MeOH, THF or a mixture thereof at temperatures around RT.Treatment of a suitable amine of structure BB-5 with tosylate ofstructure BB-33 in the presence of a suitable solvent such as MeCN attemperatures around 110° C. under microwave irradiation can be analternative procedure to provide diamino compounds of structure A-2(Scheme A1, step c).

An alternative preparation of compounds of structure A-2 may be areductive amination of a suitable aldehyde of structure BB-6 (or BB-20,respectively) with amines of structure BB-7 using standard conditionssuch as treatment with NaBH(OAc)₃ in the optional presence of AcOH (orwith NaBH₄, respectively) and in the presence of a suitable solvent suchas DCM, MeOH, THE or a mixture thereof (or TFE, respectively) attemperatures around RT (or around 35° C., respectively) (Scheme A1, stepd (or step g, respectively)).

Compounds of structure A-2 may alternatively be prepared by cleavage ofthe Boc protecting group in suitable compounds of structure A-4 (e.g.wherein R⁵ represents (C₁₋₄)alkyl, (C₂₋₃)fluoroalkyl, or(C₃₋₆)cycloalkyl-(C₀₋₄)alkylene, or the like) using a suitable acid suchas HCl or TFA in the presence of a suitable solvent such as dioxane,MeOH or DCM at temperatures around RT (Scheme A1, step f).

The reductive alkylation of the amine of structure BB-24 with ketones ofstructure BB-8 using standard conditions such as treatment withNaBH(OAc)₃ in the optional presence of AcOH and a suitable solvent suchas DCM, MeOH, THE or a mixture thereof at temperatures around RT canprovide compounds of structure A-4 (Scheme A1, step e).

Cyclic ureas of structure A-3 can be prepared by cyclisation of diaminesof structure A-2 by treatment with a suitable carbonyl transfer agentsuch as CDI in the presence of a suitable aprotic solvent such as MeCNor THE at temperatures between RT and 80° C. (Scheme A1, step h).

Alkylation of the nitrogen atom having a free valency in compounds ofstructure A-3 with a suitable halide of structure BB-9 wherein Wrepresents chlorine or bromine, in the presence of a suitable base suchas NaH or K₂CO₃ and in solvents such as THF, DMF or a mixture of both attemperatures between 0° C. and 50° C. may afford compounds of structureIa.

Alternatively, alkylation of the nitrogen atom having a free valency incompounds of structure A-3 can be achieved using Mitsunobu conditions bytreatment with a suitable alcohol of structure BB-9 wherein W representshydroxy and for instance a (cyanomethylene)trialkylphosphorane reagentin the presence of a suitable solvent such as toluene at temperaturesaround 110° C. (Scheme A1, step i).

Compounds of structure Ib, Ic, Id, Ie, If and Ig can be prepared fromsuitable precursors of structure Ia according to the synthetic routesgiven in scheme A2 below, wherein said compounds of structure Ia maycarry suitable protecting groups or functional groups as indicated.

Compounds of structure Ib wherein at least two of X, Y or Z represent Ncan be prepared from the corresponding N-SEM derivatives of compounds ofstructure Ia by cleavage of the SEM protecting group using for instancea suitable acid such as TFA in the presence of a suitable solvent suchas DCM at temperatures around RT. An additional treatment withethylenediamine in the presence of THE as solvent at temperatures around60° C. might be necessary to achieve complete cleavage of the SEMprotecting group (Scheme A2, step a). Subsequently to the TFA procedure,an additional treatment with an acid such as HCl in the presence of asuitable alcohol such as MeOH or EtOH at temperatures around 70° C. canafford the respective alkoxymethyl derivatives of structure Ic (SchemeA2, step g).

Alternatively, compounds of structure Ib wherein at least two of X, Y orZ represent N can be prepared from the corresponding Bn-protectedderivatives by cleavage of the Bn protecting group in compounds ofstructure Ia by catalytic hydrogenation using a suitable catalyst suchas Pd/C in the presence of a suitable solvent such as EtOH or MeOH andunder a hydrogen atmosphere at temperatures around RT. Catalytictransfer hydrogenation conditions using for instance ammonium formatecan be an alternative procedure (Scheme A2, step a).

Alternatively, compounds of structure Ib wherein at least two of X, Y orZ represent N can be prepared from the corresponding THP-protectedderivatives by cleavage of the THP protecting group in compounds ofstructure Ia by treatment with a suitable acid such as TFA in thepresence of a suitable solvent such as DCM at temperatures around RT(Scheme A2, step a).

Compounds of structure Ic (or Id or Ie, respectively) wherein R⁵ (or R⁸,respectively) represents methyl can be prepared by treatment with amethylating reagent such as Mel in the presence of a suitable base suchas DBU and a suitable solvent such as DMF at temperatures around RT.Treatment with Mel in the presence of Ag₂CO₃ as base and heating in asuitable solvent such as toluene at temperatures around 85° C. can be analternative procedure (Scheme A2, step b, c or d).

In compounds of structure Ib, a free NH group corresponding to X, Y or Zcan be alkylated by treatment with a suitable halide, aziridine, epoxideor tosylate of structure BB-10 in the presence of a suitable base suchas NaH, K₂CO₃ or Cs₂CO₃ and in solvents such as THF, DMF or DMA or amixture thereof at temperatures between 0° C. and 150° C. under possiblemicrowave irradiation can afford the corresponding compounds ofstructure Ic (Scheme A2, step b, c or d).

Alternatively, Mitsunobu conditions can be used by treatment with asuitable alcohol of structure BB-10 and for instance with a(cyanomethylene)trialkylphosphorane reagent in the presence of asuitable solvent such as toluene at temperatures around 110° C. (SchemeA2, step b, c or d).

Conditions for a 1,4-nucleophilic addition can alternatively be appliedby treatment with a suitable ethyl or methyl 2-alkenoate or2-nitroalkene of structure BB-10 in the presence of a suitable base suchas CsF, TEA or K₂CO₃ and a suitable solvent such as THE or DMF attemperatures between 0° C. and 60° C. (Scheme A2, step b, c or d).

Alternatively, alkoxycarbonylation (or alkylcarbamylation, respectively)can be performed by treatment with a suitable alkylchloroformate (oralkylisocyanate, respectively) of structure BB-10 in the presence of asuitable base such as TEA or DIPEA and a suitable solvent such as DCM orDMF at temperatures between 0° C. and RT. Di-alkylcarbamylation can beachieved by treatment with a suitable carbonyl transfer reagent such asCDI and a suitable amine of structure BB-10 in the presence of asuitable base such as TEA or DIPEA and a suitable solvent such as THE orDCM at temperatures around RT (Scheme A2, step b, c or d).

Alternatively, Chan-Lam conditions can be applied by treatment with asuitable boronic acid or boronic ester of structure BB-10 in thepresence of a suitable copper catalyst such as Cu(OAc)₂ and a suitableligand such as 2,2′-bipyridyl, in the presence of a suitable base suchas Na₂CO₃ and heating in a suitable solvent such as toluene ortrifluoromethylbenzene at temperatures between 70° C. and 90° C. (SchemeA2, step b, c or d).

Where suitable for the remaining substituents or functional groups inthe molecule, compounds of structure If can be prepared from compoundsof structure Ic (and sub-sequently compounds of structure Ig fromcompounds of structure If) by conventional functional grouptransformation, e.g. within the substituent R⁵, as described below(Scheme A2, step e; sub-sequently step f):

-   -   Carboxylic ester functions can be reduced by treatment with a        suitable reducing reagent such as CaBH₄ (formed in situ from        NaBH₄ and CaCl₂) in the presence of a suitable solvent such as        EtOH at temperatures between −10° C. and RT to give the        corresponding primary alcohol.    -   Nitrile functions can be reduced by treatment with a suitable        reducing reagent such as CoBH₄ (formed in situ from NaBH₄ and        CoCl₂) in the presence of a suitable solvent such as MeOH at        temperatures between 0° C. and RT; or by using a suitable        catalyst such as Raney nickel in the presence of a suitable base        such as ammonia and a suitable solvent such as MeOH at        temperatures between 0° C. and RT to give the corresponding        primary amine.    -   Carboxylic ester functions can be hydrolysed by treatment with a        suitable base such as LiOH, NaOH or KOH in the presence of water        and a suitable solvent such as THF, MeOH or EtOH or a mixture        thereof at temperatures between RT and 50° C. The resulting        carboxylic acid can subsequently be coupled with a suitable        amine by treatment with suitable activating reagents such as the        combination EDC·HCl and HOBt in the presence a suitable base        such as DIPEA and stirring in a suitable solvent such as DCM or        DMF or a mixture thereof at temperatures around RT.    -   Acetal protected aldehydes can be deprotected by acidic        treatment with aq. HCl in the presence of a suitable solvent        such as THE at temperatures between RT and 70° C. Resulting        aldehydes can subsequently react with a suitable Grignard        reagent such as alkyl magnesium bromides in the presence of a        suitable solvent such as THE at temperatures between 0° C. and        RT. Alternatively, reductive amination with suitable amines        using conditions such as treatment with NaBH(OAc)₃ in the        presence of AcOH (or NaBH₄ respectively) and in the presence of        a suitable solvent such as DCM, MeOH, THE or a mixture thereof        (or TFE respectively) at temperatures between RT and 40° C. can        afford corresponding secondary or tertiary amines.    -   A chlorine substituent can be substituted with suitable amines        in the presence of a suitable solvent such as DMF at        temperatures around 70° C.    -   A primary amide can be dehydrated by treatment with a suitable        dehydrating reagent such as Burgess reagent in the presence of a        suitable solvent such as DCM at temperatures around RT to give        the corresponding nitrile.    -   A tertiary alcohol can be dehydrated by treatment with a        suitable dehydrating reagent such as POCl₃ in the presence of a        suitable solvent such as pyridine and heating at temperatures        around 50° C. to give the corresponding alkene.    -   A Boc protected amine can be deprotected by treatment with a        suitable acid such as HCl or TFA in the presence of a suitable        solvent such as dioxane, MeOH or DCM at temperatures around RT        to release the corresponding free amine.    -   A trityl protected lactam can be deprotected by treatment with a        suitable acid such as TFA in the presence of a suitable solvent        such as H₂O at temperatures around 0° C. to release the        corresponding free lactam.    -   A 2-nitrobenzenesulfonyl protected amine can be deprotected by        treatment with a suitable solid-supported thiol such as        QuadraPure® MPA in the presence of a suitable base such as        Cs₂CO₃ and heating in a suitable solvent such as THE under        microwave irradiation at temperatures around 130° C. to give the        corresponding free amine.    -   A carbon-carbon double bond can be reduced by catalytic        hydrogenation using a suitable catalyst such as Pd/C in the        presence of a suitable solvent such as EtOAc, MeOH or a mixture        thereof at temperatures around RT to give the corresponding        saturated bond.    -   A primary or secondary amine can be acylated (or        alkylsulfonylated or dialkylsulfamylated, respectively) by        treatment with a suitable acyl chloride (or alkylsulfonyl        chloride or di-alkylsulfamyl chlorides, respectively) in the        presence of a suitable base such as TEA or DIPEA and a suitable        solvent such as DCM or DMF at temperatures between 0° C. at RT.        Alternatively, it can be alkoxycarbonylated by treatment with a        suitable chloroformate or dialkyldicarbonate reagent (or        pentafluorophenylcarbonate reagent, respectively) in the        presence of a suitable base such as TEA or DIPEA and a suitable        solvent such as DCM (or DMF, respectively) at temperatures        between 0° C. at RT (or between RT and 110° C., respectively).        Alternatively, it can be dialkylcarbamylated by treatment with a        suitable carbonyl transfer reagent such as CDI and a suitable        amine in the presence of a suitable base such as TEA or DIPEA        and a suitable solvent such as THE or DCM at temperatures around        RT. Alternatively, it can be alkylated by reductive alkylation        with aldehydes using standard conditions such as treatment with        NaBH(OAc)₃ in the presence of AcOH and in the presence of a        suitable solvent such as DCM, MeOH, THE or a mixture thereof at        temperatures between RT and 40° C. Alternatively, alkylation can        be achieved by treatment with a suitable halide in the presence        of a suitable base such as DIPEA, a catalytic amount of KI and        heating in a suitable solvent such as DMF under possible        microwave irradiation at temperature between 110° C. and 150° C.        Alternatively, a primary or secondary amine can be engaged in an        aromatic nuleophilic substitution with a suitable        (hetero)aromatic halide in the presence of a suitable base such        as DIPEA or K₂CO₃ and stirring in a suitable solvent such as        DMSO at temperatures between RT and 110° C. Alternatively,        aromatic nucleophilic substitution can be achieved by activation        of a suitable (hetero)aromatic alcohol of structure with PyBOP        in the presence of a suitable base such as DIPEA in solvents        such as DMF at temperatures around RT.    -   An alcohol can be transformed to a primary amine following the        two-step procedure: (i) Mitsunobu conditions to form a        phthalimide intermediate by treatment with phthalimide and e.g.        a (cyanomethylene)trialkylphosphorane reagent and heating in a        suitable solvent such as toluene at temperatures around 110° C.        and (ii) cleavage of the phthalimide by treatment with hydrazine        hydrate in the presence of a suitable solvent such as EtOH at        temperature around 80° C. to release the corresponding primary        amine.

Compounds of structure Ia and Ih can further be prepared according tothe synthetic routes given in scheme B below.

Compounds of structure B-1 wherein none of X, Y and Z represents NH andR¹ does not represents Boc can be prepared by treatment of amines ofstructure A-2 wherein none of X, Y and Z represents NH and R¹ does notrepresents Boc with Boc-anhydride in the presence of a suitable basesuch as TEA or DIPEA in a suitable solvent such as DCM or THE attemperatures between 0° C. and RT (Scheme B, step a).

Reductive alkylation of amines of structure B-1 with aldehydes orketones of structure BB-12 using standard conditions such as treatmentwith NaBH(OAc)₃ in the presence of AcOH (or NaBH₄, respectively) and inthe presence of a suitable solvent such as DCM, MeOH, THE or a mixturethereof (or TFE, respectively) at temperatures between RT and 40° C. canafford compounds of structure B-2 (Scheme B, step b).

Cleavage of the Boc protecting group in compounds of structure B-2wherein R¹ does not represents Boc can be performed by treatment with asuitable acid such as HCl or TFA in the presence of a suitable solventsuch as dioxane, MeOH or DCM at temperatures around RT to afforddiamines of structure B-3 (Scheme B, step c).

Cyclic ureas of structure Ia can be prepared by cyclisation of compoundof structure B-3 by treatment with a suitable carbonyl transfer agentsuch as CDI, DSC or phosgene in the presence of a suitable aproticsolvent such as MeCN at temperatures around 80° C. (Scheme B, step d).

Catalytic deuteration of (hetero)aryl groups which are substituted byone bromine or chlorine atom with a suitable catalyst such as Pd/C inthe presence of a suitable solvent such as EtOAc, CD₃OD or a mixturethereof under a deuterium atmosphere at temperatures around RT mayafford the corresponding mono-deuterated (hetero)aryl groups (Scheme B,step e).

Heteroaryl groups which are substituted by one fluorine atom in orthoposition to a ring nitrogen atom can be prepared by aromaticnucleophilic substitution of CsF on the corresponding chloro heteroarylgroup in the presence of a suitable solvent such as DMSO under possiblemicrowave irradiation at temperatures around 100° C. (Scheme B, step e).

Alkylated (hetero)aryl groups be prepared by Suzuki cross coupling of asuitable aromatic chloride with a (C₁-C₄)-alkyl boronic acid or boroxinein the presence of a suitable palladium catalyst such asPd(dppf)Cl₂·CH₂Cl₂ or PEPPSI-IPr, in the presence of a suitable basesuch as K₂CO₃ and heating in a suitable solvent such as dioxane attemperatures around 100° C. (Scheme B, step e).

Aromatic nucleophilic substitution of sodium alkoxides (or suitableamines) on suitable (hetero)aryl groups, e.g. heteroaryl groups whichare substituted by one chlorine atom in ortho position of a nitrogen, inthe presence of the corresponding alcohol as solvent (or in the presenceof a suitable solvent such as MeOH, respectively) at temperatures around80° C. (or at temperatures between 80° C. and 150° C. under microwaveirradiation, respectively) may afford e.g. the compounds of structure Ihwherein R² represents a mono-, di- or tri-substituted 5- or 6-memberedheteroaryl which is substituted by one (C₁₋₄)alkoxy substituent (orR^(21a)R^(21b)N—) (Scheme B, step e).

Alkylation of a free aromatic hydroxy group, e.g. in compounds ofstructure Ia wherein R² represents a phenyl or 5- or 6-memberedheteroaryl which is substituted by one hydroxy group, with a suitablealkyl halide, cycloalkyl halide (C₃₋₆)cycloalkyl-(C₀₋₃)alkyl halidewherein the (C₃₋₆)cycloalkyl optionally contains one ring oxygen, in thepresence of a suitable base such as NaH or K₂CO₃ and in solvents such asTHF, DMF or a mixture thereof at temperatures between 0° C. and 150° C.and under possible microwave irradiation may alternatively afford thecorresponding compounds of structure Ih. Alternatively, Mitsunobuconditions can be used by treatment for instance with a(cyanomethylene)trialkylphosphorane reagent in the presence of asuitable solvent such as toluene at temperatures around 110° C. (SchemeB, step e).

Compounds of structure Ia and Ii and Ij can be prepared according to thesynthetic route given in scheme C below.

Compounds of structure C-1 can be prepared by reductive amination ofsuitable aldehydes of structure BB-14 (or ketones of structure BB-13,respectively) with suitable amines of structure BB-15 (or diamines ofstructure BB-5, respectively) using standard conditions as set outbefore. Alternatively, NaBH₄ can be used as reducing agent in thepresence of TFE as solvent at temperatures around 40° C. according toSynthesis, 2011, 3, 490-496 (Scheme C, step b (or step a, respectively).

Alternatively, compounds of structure C-1 can be prepared by a two stepprocedure (i) reductive amination of suitable aldehydes of structureBB-4 with suitable amines of structure BB-15 using standard conditionsas set out before and (ii) subsequent reduction of the nitro group inintermediates of structure C-4 using standard conditions such ascatalytic hydrogenation with a suitable catalyst such as Pd/C in asuitable solvent such as EtOAc or EtOH or a mixture thereof (Scheme C,steps g and h).

Cyclic ureas of structure C-2 can be prepared by cyclisation of compoundof structure C-1 by treatment with a suitable carbonyl transfer agentsuch as CDI in the presence of a suitable aprotic solvent such as MeCNat temperatures around RT (Scheme C, step c).

Alkylation of the nitrogen atom having a free valency in compounds ofstructure C-2 with a suitable halide of structure BB-9 wherein Wrepresents chlorine or bromine; or using Mitsunobu conditions as set outbefore (Scheme C, step d).

Cleavage of the Boc protecting group in compounds of structure Ii can beas set out before to afford amines of structure C-3 (Scheme C, step e).

Compounds of structure Ij can be prepared by Buchwald-Hartwig crosscoupling of halides of structure BB-16 wherein W represents iodine,bromine or chloride with amines of structure C-3 in the presence of asuitable palladium catalyst such as Pd₂(dba)₃ and a suitable ligand suchas BINAP, in the presence of a suitable base such as sodiumtert-butoxide and heating in a suitable solvent such as toluene attemperatures between 100° C. and 110° C. (Scheme C, step f).

Aromatic nucleophilic substitution of amines of structure C-3 onsuitable activated halogenides of structure BB-16 wherein W representschlorine or fluorine in the presence of a suitable base such as K₂CO₃ orCsF and heating in a suitable solvent such as DMSO under possiblemicrowave irradiation at temperatures between 100° C. and 130° C. mayalternatively afford compounds of structure Ij (Scheme C, step f).

Compounds of structure Ij can alternatively be prepared following athree-step procedure: (i) aromatic nucleophilic substitution of aminesof structure C-3 on activated halides of structure BB-16 wherein Wrepresents fluorine or chlorine which is substituted for instance by oneformyl group in ortho position of the halogen atom W in the presence ofa suitable base such as CsF or K₂CO₃ and heating in a suitable solventsuch as DMSO under microwave irradiation at temperatures between 60° C.and 150° C. and (ii) subsequent decarbonylation by treatment with asuitable acid such as toluene-4-sulfonic acid and in the presence of asuitable solvent such as MeOH under possible microwave irradiation attemperatures around 120° C. and (iii) subsequent chlorination bytreatment with a chlorinating reagent such as NCS in the presence of asuitable solvent such as THE at temperatures around RT (Scheme C, stepf).

Alternatively, compounds of structure Ia can be prepared according toscheme D below.

Compounds of structure D-1 can be prepared by reductive amination ofsuitable aldehydes of structure BB-19 with suitable amines of structureBB-7 using standard conditions as set out before (Scheme D, step a).

Heating compounds of structure D-1 in a suitable solvent such as DMFunder microwave irradiation at temperatures around 120° C. canalternatively afford compounds of structure A-3 (Scheme D, step b).

Alkylation of the nitrogen atom having a free valency in compounds ofstructure A-3 (Scheme D, step c) is described in Scheme A1 (step i).

Alternatively, compounds of structure Ia which are compounds of Formula(I) wherein R⁴ represents C₁₋₄-alkyl can be prepared according to schemeE below.

Compounds of structure E-1 (or E-2, respectively) can be prepared byreductive amination of suitable ketones of structure BB-26 (or BB-27,respectively) with suitable amines of structure BB-7 using standardconditions as set out before. Alternatively, a two-step procedure can beapplied (i) condensation of suitable ketones of structure BB-26 whereinR⁴ represents (C₁₋₄)alkyl with amines of structure BB-7 in the presenceof titanium (IV) isopropoxide at temperatures around RT and (ii)subsequent reduction of the intermediate by treatment with NaBH₄ in thepresence of a suitable solvent such as EtOH, THE or a mixture thereof attemperatures between −15° C. and RT (Scheme E, step a (or step e,respectively)).

The following sequence of reactions to provide compounds of structure Ia(Scheme E, steps b, c and d) is similar to the one already described inScheme A1 (steps b, h and i).

Compounds of structure E-4 (or E-7, respectively) can be preparedfollowing a two-step procedure (i) condensation of suitable aldehydes orketones of structure BB-12 with amines of structure BB-28 (or BB-34,respectively) in the presence of AcOH and a suitable solvent such as THEor MeOH at temperatures between RT and 60° C. and (ii) subsequentreduction of the intermediate imine by treatment with NaBH₄ attemperatures between 0° C. and RT (Scheme E, step f (or step j,respectively)).

Addition of a suitable Grignard reagent of structure R⁴—MgBr, e.g.wherein R⁴ represents (C₁₋₄)alkyl, on nitriles of structure E-4 in thepresence of a suitable aprotic solvent such as THE at temperaturesbetween 0° C. and RT followed by acidic hydrolysis may afford thecorresponding ketones of structure E-5 (Scheme E, step g).

Alternatively, compounds of structure E-5 can be prepared by Heck crosscoupling of halides of structure E-7 (or E-8, respectively) with butylvinyl ether or ethyl 1-propenyl ether in the presence of a suitablepalladium catalyst such as Pd(OAc)₂ in combination with1,3-bis(diphenylphosphino)propane or 2-(di-tert-butylphosphino)biphenylas ligand, in the presence of a suitable base such as K₂CO₃ and heatingin a suitable solvent such as a mixture of DMF and H₂O or MeCN attemperatures around 100° C. The consecutive treatment with an acid suchas HCl can release the ketone (Scheme E, step m (or step n,respectively).

Compounds of structure E-6 can be prepared following a two-stepprocedure (i) condensation of suitable ketones of structure E-5 (orE-10, respectively), e.g. wherein R⁴ represents (C₁₋₄)alkyl, with aminesof structure BB-7 in the presence of titanium (IV) isopropoxide attemperatures around RT and (ii) subsequent reduction of the intermediateby treatment with NaBH₄ as set out before (Scheme E, step h (or step q,respectively)).

Cyclisation of compounds of structure E-6 by treatment with a suitablecarbonyl transfer agent such as DSC or CDT in the possible presence of asuitable base such as TEA and in a suitable aprotic solvent such as DCMor MeCN at temperatures between RT and 80° C. may alternatively affordcompounds of structure Ia (Scheme E, step i).

Compounds of structure E-8 wherein Y represents N-THP can be prepared bytreatment of compounds of structure E-7 wherein Y represents NH with3,4-dihydro-2H-pyran in the presence of a catalytic amount of TsOH and asuitable solvent such as DCM at temperatures around 40° C. (Scheme E,step k).

The THP protecting group in compounds of structure E-5 wherein Yrepresents N-THP can be cleaved by treatment with a suitable acid suchas TFA in the presence of a suitable solvent such as DCM at temperaturesaround RT to release compounds of structure E-9 wherein Y represents NH(Scheme E, step o).

Chan-Lam conditions can be applied to compounds of structure E-9 whereinY represents NH by treatment with a suitable boronic acid or boronicester of structure BB-10 in the presence of a suitable copper catalystsuch as Cu(OAc)₂ and a suitable ligand such as 2,2′-bipyridyl, in thepresence of a suitable base such as Na₂CO₃ and heating in a suitablesolvent such as toluene at temperatures between 70° C. and 90° C.(Scheme E, step p).

If not commercially available, aldehydes of structure BB-4 can beprepared according to scheme F below.

Esters of structure BB-1 wherein R^(e) represents methyl (or ethyl,respectively) can be prepared by esterification of carboxylic acids ofstructure A by treatment with a strong acid such as H₂SO₄ or HCl (whichcan be formed in situ from AcCl and MeOH (or EtOH, respectively)) andheating in a suitable alcohol such as MeOH (or EtOH, respectively) attemperatures around 80° C. (Scheme F, step a).

Protection of building blocks of structure BB-1 e.g. by treatment withSEM-Cl in the presence of a suitable base such as TEA or DIPEA and thepresence of a suitable solvent such as DCM at temperatures between 0° C.and RT may afford the corresponding compounds of structure BB-2 whereinone of X, Y or Z represents N-SEM (Scheme F, step b).

Reduction of carboxylic esters of structure BB-1 or BB-2 can be achievedfor instance by treatment with a suitable reducing reagent such as NaBH₄or CaBH₄ (formed in situ from NaBH₄ and CaCl₂) in the presence of asuitable solvent such as MeOH, EtOH or THE or a mixture thereof attemperatures between 0° C. and RT to give alcohols of structure BB-3(Scheme F, step c and d).

Oxidation of primary alcohols of structure BB-3 by treatment with asuitable oxidizing reagent such as MnO₂ in the presence of a suitablesolvent such as DCM at temperatures between RT and 45° C. can affordaldehydes of structure BB-4 (Scheme F, step e).

Alternatively, aldehydes of structure BB-4 can be prepared by protectionof building blocks of structure BB-11 wherein one of X, Y or Zrepresents NH with a suitable protecting group. The treatment forinstance with SEM-Cl under standard conditions provides building blocksof structure BB-4 wherein one of X, Y or Z represents N-SEM (Scheme F,step f).

If not commercially available, aldehydes of structure BB-19 can beprepared according to scheme G below.

Carbamates of structure BB-17 can be prepared by treatment of suitableamines of structure B (in case none of X, Y and Z represents NH) withmethylchloroformate in the presence of a suitable base such as TEA orDIPEA, catalytic amounts of DMAP and in a suitable solvent such as MeCN,DCM or DMF at temperatures between 0° C. and RT (Scheme G, step a).

Reduction of the ester function in building blocks of structure BB-17can be achieved for instance by treatment with a suitable reducingreagent as set out before to give alcohols of structure BB-18 (Scheme G,step b).

Oxidation of primary alcohols of structure BB-18 by treatment with asuitable oxidizing reagent such as MnO₂ as set out before can affordaldehydes of structure BB-19 (Scheme G, step c).

If not commercially available, aldehydes of structure BB-20 can beprepared according to scheme H below.

Aromatic nucleophilic substitution of sodium azide on suitable activatedbromides of structure C in the presence of a suitable solvent such asDMSO at temperatures around RT can provide aldehydes of structure BB-20(Scheme H, step a).

If not commercially available, amines of structure BB-24 can be preparedaccording to scheme I below.

Building blocks of structure BB-21 can be prepared by treatment ofamines of structure D wherein one of X, Y or Z represents NH and the twoothers represent N with Boc₂O in the presence of a suitable base such asTEA or DIPEA in a suitable solvent such as THE or DCM at temperaturesbetween 0° C. and RT (Scheme I, step a). Alkylation of building blocksof structure BB-21 wherein one of X, Y or Z represents NH and the twoothers represent N with suitable halides of structure R⁵—W wherein Wrepresents chlorine, bromine or iodine using conditions set out beforemay afford building blocks of structure BB-22 (Scheme I, step b).Dehydration of primary amides of structure BB-22 by treatment forinstance with Burgess reagent in a suitable solvent such as DCM attemperatures around RT can provide nitriles of structure BB-23 (SchemeI, step c). Reduction of nitriles of structure BB-23 using standardRaney nickel conditions can afford amines of structure BB-24 (Scheme I,step d).

If not commercially available, amines of structure BB-7 and ketones ofstructure BB-8 can be prepared according to the synthetic routes givenin scheme J below.

Building blocks of structure BB-29 can be prepared by standardBuchwald-Hartwig cross coupling of halides of structure R¹—W wherein Wrepresents iodine, bromine or chloride with amines of structure E(Scheme J, step a). Alternatively, building blocks of structure BB-29wherein can be prepared by standard aromatic nucleophilic substitutionof amines of structure E on activated halides of structure R¹—W whereinW represents fluorine or chlorine (Scheme J, step a). Cleavage of theketal protecting group in building blocks of structure BB-29 by acidichydrolysis in the presence of a suitable acid such as aq. HCl andheating in a suitable solvent such as THE at temperatures around 70° C.may afford ketones of structure BB-8 (Scheme J, step b). Building blocksof structure BB-30 can be prepared by standard aromatic nucleophilicsubstitution of amines of structure F on activated halides of structureR¹—W wherein W represents fluorine or chlorine (Scheme J, step c).

Alternatively, building blocks of structure BB-30 wherein R¹ representsa mono-, di- or tri-substituted phenyl which is substituted by onemethyl group at the ortho position to the connecting nitrogen can beprepared following a four-step procedure: (i) aromatic nucleophilicsubstitution of amines of structure F on halides of structure R¹—Wwherein W represents fluorine or chlorine and R¹ represents a suitablemono-, or di-substituted phenyl which is substituted by one formyl groupat the ortho position of the halogen atom W in the presence of asuitable base such as K₂CO₃ and heating in a suitable solvent such asDMSO at temperatures between 100° C. and 120° C. and (ii) subsequentreduction of the benzaldehyde derivative by treatment with a suitablereducing reagent such as NaBH₄ in the presence of a suitable solventsuch as MeOH at temperatures between 0° C. and RT and (iii) subsequentacetylation of the resulting benzyl alcohol by treatment with acetylchloride in the presence of a suitable base such as TEA and in asuitable solvent such as DCM at temperatures between 0° C. and RT and(iv) final catalytic hydrogenation of the resulting benzyl ester with asuitable catalyst such as Pd/C in the presence of a suitable solventsuch as EtOAc, MeOH or a mixture thereof at temperatures around RT(Scheme J, step c).

Alternatively, building blocks of structure BB-30 wherein R¹ representsa mono- or di-substituted phenyl or pyridine which is substituted by onedifluoromethyl group at the ortho position to the connecting nitrogencan be prepared following a two-step procedure: (i) aromaticnucleophilic substitution of amines of structure F on halides ofstructure R¹—W wherein W represents fluorine or chlorine and R¹represents a suitable mono-, or di-substituted phenyl or pyridine whichis substituted by one formyl group at the ortho position of the halogenatom W as set out before and (ii) subsequent defluorination of thebenzaldehyde derivative by treatment with a suitable fluorinatingreagent such as bis(2-methoxyethyl)aminosulfur trifluoride in thepresence of a suitable solvent such as DCM at temperatures around RT(Scheme J, step c). An alternative sequence of reactions can providecompounds of structure BB-30 wherein R¹ represents a mono- ordi-substituted phenyl which is substituted by one halogen atom at theortho position to the connecting nitrogen. A three-step procedure isfollowed (i) aromatic nucleophilic substitution of amines of structure Fon halides of structure R¹—W wherein W represents fluorine or chlorineand R¹ represents a suitable mono-, or di-substituted phenyl which issubstituted by one nitro group at the ortho position of the halogen atomW as set out before and (ii) subsequent reduction of the nitro group toan amino group as set out before and (iii) subsequent Sandmeyer rxn tointroduce a halogen atom using standard conditions. An additional Suzukior Kumada cross coupling reaction can be used to introduce an(C₁₋₄)alkyl or (C₃₋₆)cycloalkyl group at the place of the halogen atom(Scheme J, step c).

Cleavage of the Boc protecting group in building blocks of structureBB-30 can be performed to afford amines of structure BB-7 (Scheme J,step d).

Transformation of ketones of structure BB-8 to amines of structure BB-7can be achieved by reductive amination with for instance aq. ammoniaunder catalytic hydrogenation conditions using a suitable catalyst suchas Pd/C in the presence of a suitable solvent such as dioxane attemperatures around RT (Scheme J, step e).

Whenever the compounds of formula (I) are obtained in the form ofmixtures of enantiomers, the enantiomers can be separated using methodsknown to one skilled in the art: e.g. by formation and separation ofdiastereomeric salts or by HPLC over a chiral stationary phase such as aRegis Whelk-O1(R,R) (10 μm) column, a Daicel ChiralCel OD-H (5-10 μm)column, or a Daicel ChiralPak IA (10 μm), IC (5 μm) or AD-H (5 μm)column. Typical conditions of chiral HPLC are as disclosed in theexperimental part below.

The following examples are provided to illustrate the invention. Theseexamples are illustrative only and should not be construed as limitingthe invention in any way.

Experimental Part

1. Chemistry

All temperatures are stated in ° C. Commercially available startingmaterials were used as received without further purification.

Characterization of Compounds

Compounds described in the invention are characterized by LC-MS data(retention time t_(R) is given in min) and/or NMR using the conditionsdescribed below.

Analytical LC-MS:

LC-MS (Method I): Waters Acquity UPLC i-Class system with Waters i-ClassBSM binary pump, Thermo MSQ Plus MS detector and Waters Acquity PDAdetector.

Eluents (acidic conditions): A: H₂O+0.04% TFA; B: MeCN; gradient: 5%B→95% B; runtime: 1.2 min; flow: 0.8 mL/min; detection: UV/Vis+MS

Column Agilent Zorbax RRHD SB-aq, 2.1×50 mm, 1.8 μm

LC-MS (Method II): Dionex Ultimate 3000 system with Dionex HPG-3200RSbinary pump, Thermo MSQ Plus MS detector and Dionex DAD-3000RS PDAdetector.

Eluents (acidic conditions): A: H₂O+0.04% TFA; B: MeCN; gradient: 5%B→95% B; runtime: 1.5 min; flow: 4.5 mL/min; detection: UV/Vis+MS

Column Agilent Zorbax SB-aq, 4.6×50 mm, 3.5 μm

LC-MS (Method III): Dionex Ultimate 3000 system with Dionex HPG-3200SDbinary pump, Thermo MSQ Plus MS detector and Dionex DAD-3000RS PDAdetector.

Eluents (basic conditions): A: H₂O+13 mmol/L NH₄OH; B: MeCN; gradient:5% B→95% B; runtime: 1.9 min; flow: 1.6 mL/min; detection: UV/Vis+MS

Column Waters BEH C₁₈, 3.0×50 mm, 2.5 μm

LC-MS (Method IV): Waters Acquity UPLC i-Class system with Watersi-Class BSM binary pump, Thermo MSQ Plus MS detector and Waters AcquityPDA detector.

Eluents (basic conditions): A: H₂O+13 mmol/L NH₄OH; B: MeCN; gradient:5% B→95% B; runtime: 1.9 min; flow: 0.8 mL/min; detection: UV/Vis+MS

Column Waters BEH C₁₈, 2.1×50 mm, 2.5 μm

NMR Spectroscopy:

Bruker Avance HD spectrometer equipped with a 500 MHz Ultrashield™Magnet and a 5 mm DCH cryoprobe or Bruker Avance II spectrometerequipped with a 400 MHz Ultrashield™ Magnet and a BBO 5 mm probehead.Chemical shifts (S) are reported in parts per million (ppm) relative toproton resonances resulting from incomplete deuteration of the NMRsolvent, e.g. for dimethylsulfoxide δ(H) 2.49 ppm, for chloroform δ(H)7.24 ppm. The abbreviations s, d, t, q and m refer to singlet, doublet,triplet, quartet, multiplet, respectively and br to broad. Couplingconstants J are reported in Hz.

Purification of Compounds

The compounds were purified by either column chromatography onsilica-gel and/or prep. LC-MS using the conditions described below.

Column Chromatography

Column chromatography (CC) was performed using prepacked cartridges(SNAP Ultra™, SNAP KP-SIL™, SNAP KP-NH™, Isolute™ Silica II or Isolute™NH₂) from Biotage.

Preparative LC-MS:

Gilson 333/334 Prep-Scale HPLC pump equipped with Gilson LH215autosampler, Dionex SRD-3200 degasser, Dionex ISO-3100A make-up pump,Dionex DAD-3000 DAD detector and Thermo MSQ Plus Single Quadrupole MSdetector. Flow: 75 mL/min. Detection: UV/Vis and/or MS.

Additional information for the purification is summarized in the tablebelow with following definitions:

XBridge: column Waters XBridge C₁₈, 10 μm, 30×75 mm

Zorbax: column Agilent Zorbax SB-aq, 5 μm, 30×75 mm

Atlantis: column Waters Atlantis T3, 10 μm, 30×75 mm

Acidic: eluant: A=H₂O with 0.5% HCOOH, B=MeCN

Basic: eluant: A=H₂O with 0.125% NH₄OH, B=MeCN

Very lipophilic gradient: 50% B→95% B over 4 min then 95% B over 2 min

Lipophilic gradient: 30% B→95% B over 4 min then 95% B over 2 min

Normal gradient: 20% B→95% B over 4 min then 95% B over 2 min

Polar gradient: 10% B→95% B over 4 min then 95% B over 2 min

Very polar gradient: 5% B→50% B over 3 min then 50% B→95% B over 1 minand finally 95% B over 2 min

XBridge Zorbax Atlantis acidic basic acidic basic Very lipophilicgradient Method 10 Method 8  Method 9  Method 6 Lipophilic gradientMethod 4  Method 5  Method 2  Normal gradient Method 3  Method 1  Method11 Polar gradient Method 7  Very polar gradient Method 12

Abbreviations (as Used Hereinbefore or Hereinafter)

Ac acetyl

AcOH acetic acid

AIBN azobisisobutyronitrile

aq. aqueous

BINAP racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

Bn benzyl

Boc tert.-butyloxycarbonyl

Cbz benzyloxycarbonyl

CC column chromatography

CDI carbonyl diimidazole

CDT 1,1′-carbonyl-di-(1,2,4-triazole)

CPhos 2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane

dioxane 1,4-dioxane

DIPEA diisopropylethylamine

DMA dimethylacetamide

DMF dimethylformamide

DMSO dimethylsulfoxide

Dppf 1,1′-bis(diphenylphosphino)ferrocene

DSC N,N′-disuccinimidyl carbonate

EDC·HCl N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

eq equivalent(s)

Et ethyl

EtOAc ethyl acetate

EtOH ethanol

Et₂O diethylether

g gram(s)

h hour(s)

Hept heptane

HOBt 1-hydroxybenzotriazole

HPLC high performance liquid chromatography

io ionisation

LC-MS liquid chromatography-mass spectrometry

MeCN acetonitrile

MeOH methanol

mg milligram(s)

min minute(s)

mL milliliter(s)

mmol millimole(s)

MS mass spectroscopy

NaBH(OAc)₃ sodium triacetoxyborohydride

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NMR nuclear magnetic resonance spectroscopy

OAc acetate

org. organic

ON overnight

PEPPSI-IPr[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride

Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)

prep. preparative

QuadraPure© MPA mercaptophenyl amino functionalized polystyrene beads

rac racemic

RT room temperature

rxn reaction

sat. saturated

SEM 2-(trimethylsilyl)ethoxymethyl

soln. solution

TEA triethylamine

TFA trifluoroacetic acid

TFE trifluoroethanol

THE tetrahydrofuran

THP tetrahydro-2H-pyranyl

Ts p-toluenesulfonyl

t_(R) retention time

When not commercially available, the building blocks are preparedaccording to the procedures described below.

Synthesis of Building Blocks BB-1

To a soln. of carboxylic acid A (1 eq) in anh. MeOH (4 mL/mmol) wasadded AcCl (3 eq) and the rxn mixture was stirred for 2.5 h at 80° C.(see Table 1). MeOH was evaporated off and the residue was partitionedbetween a sat. aq. soln. of NaHCO₃ and EtOAc. The org. phase was washedwith a 10% aq. soln. of Na₂CO₃ and with brine, dried over MgSO₄ andconcentrated in vacuo.

TABLE 1 t_(R) [min] MS-data ¹H NMR Acid (LC/MS m/z (500 MHz, BB-1 Namereactant A method) [M + H]⁺ DMSO-d6) δ: BB-1-1 4-Nitro-2H-pyrazole-3-commercially available carboxylic acid methyl ester BB-1-25-Nitro-1H-pyrazole-4- 3-Nitro-1H- 0.55 (I) no io 14.34 (s, 1 H),carboxylic acid methyl pyrazole-4- 8.60 (s, 1 H), ester carboxylic 3.79(s, 3 H) or acid 3-Nitro-1H-pyrazole-4- carboxylic acid methyl esterBB-1-3 1-Methyl-4-nitro-1H- commercially available pyrazole-3-carboxylicacid methyl ester

Synthesis of Building Blocks BB-2

To a suspension of BB-1 (1 eq) and SEM-Cl (1.3 eq) in DCM (3.5 mL/mmol)was added dropwise DIPEA (1.5 eq) at 0° C. The rxn mixture was stirredat 0° C. for a given time (see Table 2) and quenched with a sat. aq.soln. of NaHCO₃. It was extracted with DCM, the org. phase was washedwith a sat. aq. soln. of NaHCO₃, dried over MgSO₄ and concentrated invacuo. The crude was purified by CC using Hept/EtOAc.

TABLE 2 t_(R) [min] MS-data ¹H NMR Reactant time (LC/MS m/z (500 MHz,BB-2 Name BB-1 [h] method) [M + H]⁺ DMSO-d6) δ: BB-2-1A 4-Nitro-2-(2-BB-1-1  0.25 1.06 (I) no io 8.48 (s, 1 H), 5.61 (s, 2 trimethylsilanyl-H), 3.98 (s, 3 H), 3.56 ethoxymethyl)-2H- (m, 2 H), 0.84 (m, 2 H), −0.04pyrazole-3-carboxylic (m, 9 H) acid methyl ester BB-2-1B 4-Nitro-1-(2-1.02 (I) 302.27 9.19 (s, 1 H), 5.52 (s, 2 trimethylsilanyl- H), 3.91 (s,3 H), 3.61 ethoxymethyl)-1H- (m, 2 H), 0.87 (m, 2 H), −0.03pyrazole-3-carboxylic (s, 9 H) acid methyl ester BB-2-2A 5-Nitro-1-(2-BB-1-2 0.5 1.03 (I) no io 8.19 (s, 1 H), 5.69 (s, 2 trimethylsilanyl-H), 3.82 (s, 3 H), 3.57 (m, ethoxymethyl)-1H- 2 H), 0.82 (m, 2 H), −0.06pyrazole-4-carboxylic (m, 9 H) acid methyl ester BB-2-2B 3-Nitro-1-(2-1.00 (I) 302.15 8.80 (s, 1 H), 5.54 (s, 2 trimethylsilanyl- H), 3.81 (s,3 H), 3.61 (m, ethoxymethyl)-1H- 2 H), 0.87 (m, 2 H), −0.03pyrazole-4-carboxylic (s, 9 H) acid methyl ester

Synthesis of Building Blocks BB-3

To a soln. of methyl ester BB-1 or BB-2 (1 eq) in a mixture of THE (6.3mL/mmol) and MeOH (0.8 mL/mmol) was added portionwise NaBH₄ (4 to 8 eq)at 0° C. The rxn mixture was stirred at 0° C. for a given time (seeTable 3), poured into an aq. sat. soln. of NH₄Cl and extracted withEtOAc. The org. phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

TABLE 3 Reactant t_(R) [min] MS-data ¹H NMR BB-1 or time (LC/MS m/z (500MHz, BB-3 Name BB-2 [h] method) [M + H]⁺ DMSO-d6) δ: BB-3-1A[4-Nitro-2-(2- BB-2-1A 2.5 0.92 (I) 273.91 trimethylsilanyl-ethoxymethyl)-2H- pyrazol-3-yl]-methanol BB-3-1B [4-Nitro-1-(2- BB-2-1B2.5 0.87 (I) 273.97 trimethylsilanyl- ethoxymethyl)-1H-pyrazol-3-yl]-methanol BB-3-2 [3-Nitro-1-(2- BB-2-2B 3.5 0.89 (I) no io8.06 (s, 1 H), 5.51 (s, trimethylsilanyl- 2 H), 5.39 (t, J = 5.4ethoxymethyl)-1H- Hz, 1 H), 4.66 (dd, J = pyrazol-4-yl]-methanol 5.4 Hz,2 H), 3.59 (m, 2 H), 0.87 (m, 2 H), −0.03- 0.01 (m, 9 H) BB-3-3(1-Methyl-4-nitro-1H- BB-1-3 0.5  0.37 (II) no io 8.80 (s, 1 H), 5.22(t, pyrazol-3-yl)-methanol J = 5.9 Hz, 1 H), 4.66 (d, J = 5.8 Hz, 2 H),3.88 (s, 3 H)

Synthesis of Building Blocks BB-4 Method A (Oxidation)

To a soln. of alcohol BB-3 (1 eq) in anh. DCM (10 mL/mmol) was addedportionwise MnO₂ (9 to 10 eq) at RT and the rxn mixture was stirred at agiven temperature for a given time (see Table 4). It was filtered over apad of celite and the filtrate was concentrated in vacuo.

Method B (SEM Protection)

To a soln. of BB-11 (1 eq) in anh. DMF (9 mL/mmol) was added portionwiseNaH (1.1 eq, as a 60% dispersion in mineral oil) at 0° C. The rxnmixture was stirred for 10 min at 0° C. and SEM-Cl (1.4 eq) was addeddropwise. It was allowed to reach RT, stirred for a given time (seeTable 4) at RT and partitioned between EtOAc and water. The org. phasewas washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using Hept/EtOAc.

TABLE 4 Method Reactant T [° C.] t_(R) [min] MS-data ¹H NMR BB-3 or time(LC/MS m/z (500 MHz, BB-4 Name BB-11 [h] method) [M + H]⁺ DMSO-d6) δ:BB-4-1A 4-Nitro-2-(2- BB-3-1A A 1.04 (I) no io 10.28 (s, 1 H), 8.52 (s,trimethylsilanyl- 45   1 H), 5.74 (s, 2 H), ethoxymethyl)-2H- 18   3.60(m, 2 H), 0.85 pyrazole-3-carbaldehyde (m, 2 H), −0.05 (s, 9 H) BB-4-1B4-Nitro-1-(2- BB-3-1B A 0.79/0.99 (I)   no io 10.25 (s, 1 H), 9.20 (s,trimethylsilanyl- RT 1 H), 5.57 (s, 2 H), ethoxymethyl)-1H- 24   3.62(m, 2 H), 0.88 pyrazole-3-carbaldehyde (m, 2 H), −0.02 (m, 9 H) BB-4-23-Nitro-1-(2- BB-3-2 A 1.00 (I) no io 10.14 (s, 1 H), 8.82 (s,trimethylsilanyl- RT 1 H), 5.58 (s, 2 H), ethoxymethyl)-1H- 18   3.62(m, 2 H), 0.88 pyrazole-4-carbaldehyde (m, 2 H), −0.02 (m, 9 H) BB-4-31-Methyl-4-nitro-1H- BB-3-3 A   0.35 (III) no io 10.23 (s, 1 H), 8.98(s, pyrazole-3-carbaldehyde 45   1 H), 4.00 (s, 3 H) 3.5 BB-4-45-Nitro-3-(2- BB-11-1 B  0.89 289.99 10.28 (s, 1 H), 8.39 (s,trimethylsilanyl- RT (hydrate) 1 H), 5.70 (s, 2 H), ethoxymethyl)-3H-0.5 3.58 (m, 2 H), 0.88 imidazole-4- (m, 2 H), −0.03-0.02 carbaldehyde(m, 9 H) BB-4-5 1-Methyl-3-nitro-1H- commercially availablepyrazole-4-carbaldehyde

Synthesis of Building Blocks BB-5 Synthesis of5-aminomethyl-3-benzyl-3H-[1,2,3]triazol-4-ylamine (BB-5-2) Step A:Cyclocondensation (see Table 5)

A suspension of benzyl azide (1 eq), malononitrile (1.4 eq) and K₂CO₃ (4eq) in DMSO (1.4 mL/mmol) was stirred at RT for 18 h. The rxn mixturewas partitioned between EtOAc and H₂O. The org. phase was washed withH₂O and brine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc.

TABLE 5 t_(R) [min] MS-data (LC/MS m/z BB-5A Name method) [M + H]⁺BB-5-2A 5-Amino-1-benzyl-1H- 0.67 (II) 200.19[1,2,3]triazole-4-carbonitrile

Step B: Nitrile Reduction (See Table 6)

Nitrile BB-5A (1 eq) was dissolved in a 7M soln. of NH₃ in MeOH (7mL/mmol). The flask was evacuated three times and refilled withnitrogen. Raney nickel (0.1 eq) was added at 0° C. and the temperaturewas allowed to reach RT. The flask was evacuated and refilled threetimes with hydrogen. The suspension was stirred under a hydrogenatmosphere for 11 h and filtered over a pad of Celite. The cake waswashed with EtOAc and MeOH and the filtrate was concentrated in vacuo.

TABLE 6 t_(R) [min] MS-data Reactant (LC/MS m/z BB-5 Name BB-5A method)[M + H]⁺ BB-5-1 4-Aminomethyl-1-methyl- commercially available1H-pyrazol-3-amine BB-5-2 5-Aminomethyl-3-benzyl- BB-5-2A 0.41 (II)204.20 3H-[1,2,3]triazol-4-ylamine

Building Blocks BB-6

TABLE 7 BB-6 Name BB-6-1 3-Amino-1-methyl-1H- commercially availablepyrazole-4-carbaldehyde

Synthesis of Building Blocks BB-7 Method A: Boc Cleavage from BB-30

To a soln. of intermediate BB-30 (1 eq) in DCM (4 mL/mmol) was addeddropwise TFA (1 mL/mmol) and the rxn mixture was stirred for 1 h to 18 hat RT (see Table 8). It was basified with a 1M aq. soln. of NaOH untilpH 12-13 and extracted with DCM. The combined org. phases were driedover MgSO₄ and concentrated in vacuo.

Method B: Reductive Amination from BB-8

To a soln. of ketone intermediate BB-8 (1 eq) in dioxane (9.1 mL/mmol)was added a 25% aq. soln. of NH₄OH (36 to 38 eq) and H₂O (0.35 mL/mmol).The flask was evacuated three times and refilled with nitrogen. Wet Pd/C(0.03 to 0.06 eq) was added and the flask was evacuated and refilledthree times with hydrogen. The suspension was stirred under a hydrogenatmosphere for 24 to 48 h (see Table 8) and filtered over a pad ofCelite. The cake was washed with dioxane and MeOH and the filtrate wasconcentrated in vacuo. The crude was purified by CC using DCM/MeOH orHept/EtOAc.

Method B2: Reductive Amination from BB-8

To a soln. of ketone intermediate BB-8 (1 eq) and ammonium acetate (10eq) in MeOH (5 mL/mmol) was added AcOH (2 eq). The rxn mixture wasstirred for 2 h at RT, NaBH(OAc)₃ (2 eq) was added and the mixture wasstirred at RT for 2 h. MeOH was evaporated and the residue waspartitioned between a 1M aq. soln. of NaOH and DCM. The org. phase wasdried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc/MeOH.

TABLE 8 Reactant t_(R) [min] MS-data BB-30 or (LC/MS m/z BB-7 Name BB-8Method method) [M + H]⁺ BB-7-1 1-(2-Fluoro-6-methyl-phenyl)- BB-30-1 A0.62 (I) 209.21 piperidin-4-ylamine BB-7-2 2′-Methoxy-4′-methyl-3,4,5,6-BB-8-2 B 0.51 (I) 222.27 tetrahydro-2H-[1,3′]bipyridinyl- 4-ylamineBB-7-3 1-(2-Fluoro-6-methyl-phenyl)- BB-30-2 A 0.65 (I) 223.194-methyl-piperidin-4-ylamine BB-7-4 1-(2-Fluoro-6-methyl-phenyl)-BB-30-3 A 0.65 (I) 209.28 3-methyl-pyrrolidin-3-ylamine BB-7-5(R)-1-(2-Fluoro-6-methyl- BB-30-4 A 0.60 (I) 195.22phenyl)-pyrrolidin-3-ylamine BB-7-7 1-(2-Difluoromethyl-6-fluoro-BB-30-6 A 0.65 (I) 245.39 phenyl)-piperidin-4-ylamine BB-7-81-(2-Chloro-6-fluoro-phenyl)- BB-30-7 A 0.61 (I) 229.11piperidin-4-ylamine BB-7-9 1-(2-Cyclopropyl-6-fluoro- BB-30-8 A 0.70 (I)235.18 phenyl)-piperidin-4-ylamine BB-7-10 4′-Difluoromethyl-2′-methoxy-BB-30-9 A 0.61 (I) 258.01 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-ylamine BB-7-11 1-(2-Bromo-6-fluoro-phenyl)-BB-30-6C A 0.65 (I) 273.20 piperidin-4-ylamine BB-7-122′-Methoxy-4′-trifluoromethyl- BB-8-6  B1 0.65 (I) 276.213,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-ylamine BB-7-134′-Chloro-2′-methoxy-3,4,5,6- BB-8-7  B2 0.58 (I) 241.92tetrahydro-2H-[1,3′]bipyridinyl- 4-ylamine

Synthesis of Building Blocks BB-8

To a soln. of ketal intermediate BB-29 (1 eq) in anh. THE (3 mL/mmol)was added a 1M aq. soln. of HCl (2 to 2.5 mL/mmol) at RT (see Table 9).The rxn mixture was heated to 70° C. and stirred for 3 to 24 h. It wasquenched with a sat. aq. soln. of NaHCO₃ or a 1M aq. soln. of NaOH andextracted with EtOAc or DCM. The combined org. phases were washed withbrine, dried over MgSO₄ and concentrated in vacuo. When necessary, thecrude was purified by CC using Hept/EtOAc.

TABLE 9 t_(R) [min] MS-data Reactant (LC/MS m/z BB-8 Name BB-29 method)[M + H]⁺ BB-8-1 1-(2-Fluoro-6-methyl-phenyl)- BB-29-1 0.94 (I) 208.19piperidin-4-one BB-8-2 2′-Methoxy-4′-methyl-2,3,5,6- BB-29-2 0.78 (I)221.24 tetrahydro-[1,3′]bipyridinyl- 4-one BB-8-31-(2-Fluoro-6-methyl-phenyl)- BB-29-3 0.96 (I) 222.25 azepan-4-oneBB-8-4 1-(2-Fluoro-6-methyl-phenyl)- BB-29-4 0.95 (I) 208.26piperidin-3-one BB-8-6 2′-Methoxy-4′-trifluoromethyl- BB-29-5 0.96 (I)275.15 2,3,5,6-tetrahydro- [1,3′]bipyridinyl-4-one BB-8-74′-Chloro-2′-methoxy-2,3,5,6- BB-29-6 0.87 (I) 241.11tetrahydro-[1,3′]bipyridinyl- 4-one

Synthesis of Building Blocks BB-9 Method A: Benzylic Bromination

A suspension of methyl-heteroarene (1 eq) in chlorobenzene (4 mL/mmol)was heated to 50° C. and NBS (1.3 eq) was added portionwise at 50° C.(see Table 13). The flask was purged with argon and AIBN (0.1 eq) wasadded in one portion. The rxn mixture was heated to 80° C. and stirredfor 6 h. After cooling to RT, the mixture was diluted with Et₂O andwashed with a 1 M aq. soln. of HCl. The org. phase was washed withbrine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc.

Method B: Multi-Step Step B1: O-Alkylation Via Mitsunobu (See Table 10)

To a soln. of methyl ester (1 eq) and 2-propanol (1.5 eq) in toluene(1.5 mL/mmol) was added a 1M soln. of(tributylphosphoranylidene)acetonitrile in toluene (2 eq) under argon.The rxn mixture was heated to 110° C. and stirred for 2 h. It wasquenched with water and extracted with DCM. The combined org. phaseswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using Hept/EtOAc.

TABLE 10 t_(R) [min] MS-data Carboxylic Method/ (LC/MS m/z BB-9A Nameacid reactant Step method) [M + H]⁺ BB-9-13A 2,4-Difluoro-6-isopropoxy-2,4-Difluoro-6- B1 0.89 (II) 231.10 benzoic acid methyl esterhydroxybenzoic acid methyl ester

Step B2: Methyl/Ethyl Ester Reduction Using CaCl₂/NaBH₄ (See Table 13)

To a soln. of methyl or ethyl ester (1 eq) in anh. EtOH (15 mL/mmol) wasadded CaCl₂ (0.3 eq) and the rxn mixture was cooled to −10° C. NaBH₄(2.5 eq) was added portionwise and the mixture was stirred for 30 min at−10° C. and for 1.5 h at 70° C. It was quenched at 0° C. with water andEtOH was evaporated off. The residue was partitioned between EtOAc andwater and the aq. phase was further extracted with EtOAc. The combinedorg. phases were washed with brine, dried over MgSO₄ and concentrated invacuo. When necessary the crude was purified by CC using DCM/MeOH.

Step B3: Methyl/Ethyl Ester Reduction Using LiAlH₄ (See Table 13)

To a soln. of methyl or ethyl ester (1 eq) in anh. THE (4.5 to 7mL/mmol) was added dropwise at 0° C. a 2.4 M soln. of LiAlH₄ in THE (1eq). The rxn mixture was stirred for 1.5 h at 0° C., quenched with asat. aq. soln. of NH₄Cl and extracted with EtOAc. The combined org.phases were dried over MgSO₄ and concentrated in vacuo. When necessarythe crude was purified by CC using EtOAc.

Method C: Multi-Step Step C1: Nucleophilic Aromatic Substitution (SeeTable 11)

To a soln. of halo-heteroarene (1 eq) in anh. THE (5 mL/mmol) was addeddropwise at 0° C. a 2M soln. of lithium isopropoxide in THE (1.05 eq).The rxn mixture was stirred for 1 h at 0° C. and poured into a 1M aq.soln. of HCl. The aq. soln. was neutralized with a sat. aq. soln. ofNaHCO₃ and extracted with EtOAc. The combined org. phases were washedwith brine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc.

TABLE 11 Halo- t_(R) [min] MS-data heteroarene Method/ (LC/MS m/z BB-9AName reactant Step method) [M + H]⁺ BB-9-19A 6-Chloro-4-isopropoxy-4,6-dichloropyridazine- C1 0.88 (I) 259.17 pyridazine-3-carboxylic3-carboxylic acid methyl acid isopropyl ester ester

Step C2: Hydrogenation (See Table 12)

To a soln. of intermediate BB-9A (1 eq) in EtOH (4 mL/mmol) was addedammonium formate (2 eq) and the rxn mixture was flushed with nitrogen.Wet Pd/C (0.05 eq) was added and after inertising with nitrogen the rxnmixture was heated to 60° C. and stirred for 1 h. It was filtered over apad of Celite, the cake was washed with MeOH and the filtrate wasconcentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

TABLE 12 Halo- t_(R) [min] MS-data heteroarene Method/ (LC/MS m/z BB-9BName reactant Step method) [M + H]⁺ BB-9-19B 4-Isopropoxy-pyridazine-BB-9-19A C2 0.74 (I) 225.05 3-carboxylic acid isopropyl ester

Final Step C3: Ester Reduction (See Table 13)

To a soln. of ester intermediate 11-91 (1 eq) in anh. EtOH (15.8mL/mmol) was added CaCl₂ (0.3 eq) and the rxn mixture was cooled to −10°C. NaBH₄ (2.5 eq) was added portionwise and the mixture was stirred for30 min at −10° C. and for 3.5 h at RT. It was quenched at 0° C. withwater and EtOH was evaporated off. The residue was partitioned betweenEtOAc and water and the aq. phase was further extracted with EtOAc. Thecombined org. phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo.

TABLE 13 t_(R) [min] MS-data ¹H NMR (LC/MS m/z (500 MHz, BB-9 NameReactant Method/Step method) [M + H]⁺ DMSO-d6) δ: BB-9-12-(Trifluoromethyl) commercially available benzyl bromide BB-9-22-Bromomethyl-3- 2-Methyl-3- A 0.76 (II) no io 9.03 (d, J = 2.2trifluoromethyl-pyrazine trifluoromethyl Hz, 1 H), 8.84 pyrazine (d, J =2.3 Hz, 1 H), 4.84 (d, J = 0.9 Hz, 2 H) BB-9-3 (4-Trifluoromethyl-commercially available pyridin-3-yl)-methanol BB-9-4[3-(Trifluoromethyl) pyridin-2-yl]methanol BB-9-5 1-(Bromomethyl)-2-cyclopropyloxybenzene BB-9-6 2-(Trifluoromethyl) benzyl alcohol BB-9-72-(Chloromethyl)-3- (trifluoromethyl)pyridine BB-9-8 2-Bromo-6-(trifluoromethyl) benzylbromide BB-9-9 (2-Cyclopropylphenyl) methanolBB-9-10 1-(Bromomethyl)-2- isopropylbenzene BB-9-11 2-(Trifluoromethoxy)benzyl bromide BB-9-12 2-Chlorobenzyl bromide BB-9-13 (2,4-Difluoro-6-BB-9-13A B3 0.78 (II) no io 6.41-6.47 (m, 2 isopropoxy-phenyl)- H), 4.70(d, J = methanol 1.5 Hz, 2 H), 4.58 (m, 1 H), 1.40-1.45 (m, 6 H) BB-9-14[2-Methyl-4- commercially available (trifluoromethyl)-1,3-thiazol-5-yl]methanol hydrochloride BB-9-15 1-(2-Trifluoromethyl-phenyl)-ethanol BB-9-16 2-(Bromomethyl)phenyl acetate BB-9-17(4-Isopropyl-pyrimidin- 4-Isopropyl B2 0.47 (II) 153.46 5-yl)-methanolpyrimidine-5- carboxylic acid ethyl ester BB-9-18 (2-Ethoxy commerciallyavailable phenyl)methanol BB-9-19 (4-Isopropoxy-pyridazin BB-9-19B C30.34 (I)  169.08 -3-yl)-methanol

Synthesis of Building Blocks BB-10 Method A Step A: Carboxylic AcidReduction (See Table 14)

To a soln. of carboxylic acid (1 eq) in anh. THE (10 mL/mmol) was added4-methylmorpholine (2 eq) and ethyl chloroformate (2 eq) at −10° C. Themixture was stirred for 1 h at −10° C. and NaBH₄ (3 eq) was added in oneportion. It was allowed to warm to 0° C. over 1 h, quenched with waterand extracted with DCM. The org. phase was washed with H₂O and brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing DCM/MeOH.

Step B: Appel Rxn (See Table 15)

To a soln. of intermediate BB-10A (1 eq) in DCM (5.2 mL/mmol) was addedCBr₄ (1.5 eq) and diphenyl-2-pyridylphosphine (1.5 eq) at 0° C. The rxnmixture was stirred at 0° C. for 10 min and at RT for 1 h. It waspartitioned between DCM and a 5% aq. soln. of citric acid and the org.phase was washed with brine, dried over MgSO₄ and concentrated in vacuo.The crude was purified by CC using Hept/EtOAc.

Method B Step A: Sulfonylation (See Table 14)

A soln. of amino alcohol (1 eq) and TEA (3 eq) in DCM (5 mL/mmol) wascooled to 0° C. and 2-nitro benzenesulfonyl chloride (1.2 eq) was addeddropwise at 0° C. The rxn mixture was allowed to slowly reach RT andstirred for 1 h. It was diluted with DCM and washed with a sat. aq.soln. of NaHCO₃ and with brine. The org. phase was dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

Step B: Aziridine Formation (See Table 15)

To a stirred soln. of amino alcohol derivative (1 eq) and TEA (2 eq) inDCM (3 mL/mmol) was added dropwise at 0° C. methanesulfonyl chloride(1.05 eq). The rxn mixture was allowed to warm to RT and stirred for 45min. It was partitioned between DCM and H₂O and the org. phase was driedover MgSO₄ and concentrated in vacuo. The crude was dissolved in THE(4.2 mL/mmol) and TEA (2 eq) was added. The rxn mixture was stirred atRT for 18 h and at 50° C. for 30 min and partitioned between DCM andH₂O. The org. phase was dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using Hept/EtOAc.

TABLE 14 t_(R) [min] MS-data ¹H NMR Method (LC/MS m/z (500 MHz, BB-10AName Reactant method) [M + H]⁺ DMSO-d6) δ: BB-10-1A (2,2,2-Trifluoro-1-A (step A) 7.43 (d, J = 9.2 Hz, hydroxymethyl- 2-{[(tert-Butoxy) 1 H),5.07 (t, J = 5.9 ethyl)-carbamic acid carbonyl]amino}- Hz, 1 H),4.11-4.19 tert-butyl ester 3,3,3-trifluoro (m, 1 H), 3.64 (m, 1 H),propanoic acid 3.51 (m, 1 H), 1.41 (s, 9 H) BB-10-2A 4-Chloro-N-(2-commercially available hydroxy-1,1- dimethylethyl) benzene sulfonamideBB-10-3A N-(2-Hydroxy-1,1- B (step A) 0.68 (II) 275.04 8.11-8.13 (m, 1H), dimethyl-ethyl)-2- 2-Amino-2-methyl- 7.92-7.95 (m, 1 H),nitro-benzene 1-propanol 7.81-7.87 (m, 2 H), sulfonamide 7.59 (s, 1 H),4.94 (t, J = 5.7 Hz, 1 H), 3.24 (d, J = 5.7 Hz, 2 H), 1.06 (s, 6 H)

TABLE 15 Method t_(R) [min] MS-data ¹H NMR Reactant (LC/MS m/z (500 MHz,BB-10 Name BB-10A method) [M + H]⁺ DMSO-d6) δ: BB-10-1 (3-Bromo-1,1,1- A(step B) 7.79 (d, J = 9.4 Hz, trifluoropropan- BB-10-1A 1 H), 4.41-4.48(m, 1 H), 2-yl)-carbamic acid 3.78 (dd, J₁ = 10.6 Hz, tert-butyl esterJ₂ = 3.5 Hz, 1 H), 3.46 (dd, J₁ = J₂ = 10.6 Hz, 1 H), 1.42 (s, 9 H)BB-10-2 1-(4-Chloro-benzene B (step B) 0.84 (II) 246.11 7.90 (d, J = 8.8Hz, sulfonyl)-2,2- BB-10-2A 2 H), 7.71 (d, J = 8.6 dimethyl-aziridineHz, 2 H), 2.53 (s, 2 H), 1.47 (s, 6 H) BB-10-3 2,2-Dimethyl-1-(2-nitro-B (step B) 0.87 (I) 257.07 benzenesulfonyl)- BB-10-3A aziridine BB-10-4(R)-3-Chloro-1-trityl- Prepared 1.09 (I) 348.06 7.12-7.40 (m, 15 H),azetidin-2-one according to 5.13 (dd, J₁ = 5.1 J. Heterocyclic Hz, J₂ =2.0 Hz, 1 H), Chem., 2006, 3.78 (dd, J₁ = 6.4 Hz, 43, 11-19. J₂ = 5.1Hz, 1 H), 3.32 (m, 1 H)

Building blocks BB-11, BB-12, BB-13, BB-14, BB-15 and BB-16

TABLE 16 Name BB-11 BB-11-1 5-Nitro-1H-imidazole-4-carbaldehydecommercially BB-12 BB-12-1 3-Trifluoromethyl-2-formylpyridine availableBB-12-2 6-Chloro-3-(trifluoromethyl)picolinaldehyde BB-12-32-Fluoro-6-(trifluoromethyl)benzaldehyde BB-12-42-(Trifluoromethyl)benzaldehyde BB-12-5 2-Cyclopropylbenzaldehyde BB-13BB-13-1 N-Boc-3-pyrrolidinone BB-13-2 N-Boc-4-piperidone BB-14 BB-14-13-Amino-1-methyl-1H-pyrazole-4-carbaldehyde BB-15 BB-15-1tert-Butyl-4-aminoazepane-1-carboxylate BB-15-2 tert-Butyl4-aminopiperidine-1-carboxylate BB-16 BB-16-1 2-Bromo-3-fluorotolueneBB-16-2 2-Bromo-1,3-dimethylbenzene BB-16-32-Bromo-1-methoxy-3-methylbenzene BB-16-4 Isopropyl chloroformateBB-16-5 2,3-Difluorobenzonitrile BB-16-63-Bromo-2-fluoro-4-methylpyridine BB-16-73-Bromo-2-methoxy-4-methylpyridine BB-16-8 2-Bromo-3-fluoropyridineBB-16-9 2-Bromo-3-methylpyridine BB-16-10 2-Bromo-3-methoxypyridineBB-16-11 3-Bromo-4-methylpicolinonitrile BB-16-123-Bromo-4-fluoro-2-methylpyridine BB-16-13 3-Bromo-2,4-dimethoxypyridineBB-16-14 5-Bromo-4-methoxy-6-methylpyrimidine BB-16-155-Bromo-4,6-dimethoxypyrimidine BB-16-165-chloro-1,3-dimethyl-1H-pyrazole-4-carbonitrile BB-16-175-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde BB-16-18 Cyclopropylchloroformate BB-16-19 2-Bromo-3-fluorobenzotrifluoride BB-16-202-Bromo-1-fluoro-3-(trifluoromethoxy)benzene BB-16-212-Bromo-3-chlorotoluene BB-16-22 1-Bromo-2-isopropylbenzene BB-16-231-Bromo-2-cyclopropylbenzene BB-16-24 2-Bromo-1-chloro-3-fluorobenzeneBB-16-25 1-Bromo-2,6-difluorobenzene BB-16-262-Bromo-1-ethyl-3-fluorobenzene BB-16-272-Bromo-1-(difluoromethyl)-3-fluorobenzene BB-16-282-Bromo-1-cyclopropyl-3-fluorobenzene

Synthesis of Building Blocks BB-17

To a soln. of amines B (1 eq, see Table 17) and DIPEA (2.5 eq) in MeCN(5 mL/mmol) was added DMAP (0.2 eq) and methylchloroformate (2.5 eq) at0° C. The rxn mixture was stirred for 5 min at 0° C. and for 3 h at RT.MeOH (3 mL/mmol) was added followed by a 1 M aq. soln. of NaOH (1.7 eq).The rxn mixture was stirred for 1.5 h at RT and the volatiles wereevaporated. The residue was diluted with EtOAc and washed successivelywith a 10% aq. soln. of citric acid, a sat. aq. soln. of NaHCO₃ andbrine. The org. phase was dried over MgSO₄ and concentrated in vacuo.The crude was purified by CC using Hept/EtOAc.

TABLE 17 Amino- t_(R) [min] MS-data ¹H NMR (hetero)arene (LC/MS m/z (500MHz, BB-17 Name reactant B method) [M + H] ⁺ DMSO-d6) δ: BB-17-15-Methoxycarbonylamino- 5-Amino-2-methyl-1,3- 0.56 (II) 229.13 10.12 (s,1 H), 4.20 2-methyl-oxazole-4- oxazole-4-carboxylic (q, J = 7.1 Hz,carboxylic acid ethyl ester acid ethyl ester 2 H), 3.67 (s, 3 H), 2.39(s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H)

Synthesis of Building Blocks BB-20

To a soln. of bromides C (1 eq) in DMSO (2.5 mL/mmol) was added NaN₃(1.5 eq) at RT. The rxn mixture was stirred at RT for 5 h (see Table18Error! Reference source not found.) and quenched with H₂O. It wasextracted with EtOAc and the combined org. phases were dried over MgSO₄and concentrated in vacuo.

TABLE 18 Bromo- t_(R) [min] MS-data (hetero)arene (LC/MS m/z BB-20 Namereactant C method) [M + H]⁺ BB-20-1 5-Azido-2-methyl- 5-Bromo-2- 0.56(II) 169.04 thiazole-4- methylthiazole-4- carbaldehyde carbaldehyde

Synthesis of Building Blocks BB-18

A 2.4 M soln. of LiAlH₄ in THE (1 eq) was diluted with anh. THE (2mL/mmol) and cooled to −10° C. A soln. of ethyl ester BB-17 (1 eq, seeTable) in anh. THE (2 mL/mmol) was added dropwise at −10° C. The rxnmixture was allowed to warm from −10° C. to 5° C. over 1 h and quenchedsuccessively at 0° C. with ice water, with a 2M aq. soln. of NaOH andwith ice water. The suspension was diluted with THE, stirred for 30 minat RT, filtered over a pad of celite and the filtrate was concentratedin vacuo. The crude was purified by CC using DCM/MeOH.

TABLE 19 t_(R) [min] MS-data ¹H NMR Reactant (LC/MS m/z (500 MHz, BB-18Name BB-17 method) [M + H]⁺ DMSO-d6) δ: BB-18-1 (4-Hydroxymethyl-2-BB-17-1 0.37 (II) 187.14 9.47 (s, 1 H), 4.92 methyl-oxazol-5-yl)- (t, J= 5.6 Hz, carbamic acid 1 H), 4.16 (d, methyl ester J = 5.7 Hz, 2 H),3.65 (s, 3 H), 2.32 (s, 3 H)

Synthesis of Building Blocks BB-19

To a soln. of alcohol BB-18 (1 eq, see Table) in anh. DCM (10 mL/mmol)was added portionwise MnO₂ (9 eq) at RT and the rxn mixture was stirredat 45° C. for 4 h. It was filtered over a pad of celite and the filtratewas washed with a sat. aq. soln. of NaHCO₃ and brine, dried over MgSO₄and concentrated in vacuo.

TABLE 20 t_(R) [min] MS-data ¹H NMR Reactant (LC/MS m/z (500 MHz, BB-19Name BB-18 method) [M + H]⁺ DMSO-d6) δ: BB-19-1 (4-Formyl-2-methyl-BB-18-1 0.44 (II) 185.17 11.10 (s, 1 H), 9.81 oxazol-5-yl)-carbamic (s,1 H), 3.74 (s, 3 acid methyl ester H), 2.39 (s, 3 H)

Synthesis of Building Blocks BB-21

To a soln. of amines D (1 eq, see Table 20) and TEA (3 eq) in THE (10mL/mmol) was added Boc₂O (1.1 eq) at 0° C. The rxn mixture was stirredat 0° C. for 10 min and at RT for 18 h. It was partitioned between DCMand H₂O and the aq. phase was extracted with DCM. The combined org.phases were washed with brine, dried over MgSO₄ and concentrated invacuo.

TABLE 20 Amino- t_(R) [min] MS-data ¹H NMR (hetero)arene (LC/MS m/z (500MHz, BB-21 Name reactant D method) [M + H]⁺ DMSO-d6) δ: BB-21-1(5-Carbamoyl-1H- 4-Amino-1H-1,2,3- 0.59 (II) no 14.70 (s br, 1 H), 9.03[1,2,3]triazol-4-yl)- triazole-5- (s, 1 H), 7.88 (s, 1 H), carbamic acidtert- carboxamide 7.56 (s, 1 H), 1.48 (s, 9 H) butyl ester

Synthesis of Building Blocks BB-22

NaH (3 eq, as a 60% dispersion in mineral oil) was added portionwise at0° C. to a soln. or suspension of intermediate BB-21 (1 eq) in THE (10mL/mmol). The suspension was stirred at RT for 20 min and Mel (1.1 eq)was added at 0° C. The rxn mixture was stirred at 0° C. for 10 min andat RT for 48 h (see Table 21). When necessary to reach completion of therxn, extra amounts of NaH (1 eq) and/or Mel (0.3 eq) were needed. Therxn mixture was quenched with half sat. aq. soln. of NaHCO₃ at 0° C. andextracted with EtOAc. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified byprecipitation of the impurities from a soln. of the crude in DCM/MeOHand addition of Et₂O.

TABLE 21 t_(R) [min] MS-data ¹H NMR Reactant (LC/MS m/z (500 MHz, BB-22Name BB-21 method) [M + H]⁺ DMSO-d6) δ: BB-22-1 (5-Carbamoyl-2-methyl-BB-21-1 0.61 (II) 242.19 8.89 (s, 1 H), 2H-[1,2,3]triazol- 7.84 (s, 1H), 4-yl)-carbamic acid 7.60 (s, 1 H), 4.10 tert-butyl ester (s, 3 H),1.44 (s, 9 H)

Synthesis of Building Blocks BB-23

To a stirred soln. of amide intermediate BB-22 (1 eq) in DCM (10mL/mmol) was added portionwise Burgess' reagent (3 eq) under argon. Therxn mixture was stirred at RT for 18 h (see Table 22) and partitionedbetween DCM and H₂O. The org. phase was washed with brine, dried overMgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc.

TABLE 22 t_(R) [min] MS-data ¹H NMR Reactant (LC/MS m/z (500 MHz, BB-23Name BB-22 method) [M + H]⁺ DMSO-d6) δ: BB-23-1 (5-Cyano-2-methyl-2H-BB-22-1 0.74 (II) 224.12 10.38 (s, 1 H), [1,2,3]triazol-4- 4.16 (s, 3H), yl)-carbamic acid tert- 1.48 (s, 9 H) butyl ester

Synthesis of Building Blocks BB-24

Nitrile BB-23 (1 eq) was dissolved in a 7M soln. of NH₃ in MeOH (7mL/mmol). The flask was evacuated and refilled with nitrogen. Raneynickel (0.1 eq) was added at 0° C. and the temperature was allowed toreach RT. The flask was evacuated and refilled with hydrogen. Thesuspension was stirred under a hydrogen atmosphere at RT for 4 h (seeTable 23) and filtered over a pad of Celite. The cake was washed withMeOH and the filtrate was concentrated in vacuo.

TABLE 23 t_(R) [min] MS-data ¹H NMR Reactant (LC/MS m/z (500 MHz, BB-24Name BB-23 method) [M + H]⁺ DMSO-d6) δ: BB-24-1 (5-Aminomethyl-2-methyl-BB-23-1 0.45 (II) 228.17 9.07 (s br, 1 H), 2H-[1,2,3]triazol- 3.99 (s, 3H), 4-yl)-carbamic acid 3.58 (s, 2 H), tert-butyl ester 1.43 (s, 9 H)

Synthesis of Building Blocks BB-25 Method A (Pentafluorophenyl Ester)

A soln. of the appropriate alcohol (1 eq) andbis(pentafluorophenyl)carbonate (1.2 eq) in MeCN (0.55 mL/mmol) wascooled to 0° C. and Et₃N (3.2 eq) was added dropwise. The rxn mixturewas allowed to reach RT and stirred for 18 h (see Table 24). The mixturewas concentrated in vacuo and the residue was purified by CC usingDCM/MeOH and/or by prep. LC-MS using method 3.

Method B (Cyclisation)

A soln. of the appropriate hydrazide (1 eq) and CDI (1.5 eq) in anh.Dioxane (4.2 mL/mmol) was heated to 85° C. and stirred for 18 h. Thesolvent was evaporated under reduced pressure and the residue waspartitioned between EtOAc and H₂O. The org. phase was washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc.

TABLE 24 t_(R) [min] MS-data ¹H NMR Method Reactant (LC/MS m/z (500 MHz,BB-25 Name alcohol/hydrazide method) [M + H]⁺ DMSO-d6) δ: BB-25-1Carbonic acid A 0.86 (II) no io 5.65 (m, 1 H), 4.87 oxetan-3-yl ester3-Hydroxy oxetane (m, 2 H), 4.65 (ddd, pentafluorophenyl J₁ = 0.9 Hz, J₂= ester 4.7 Hz, J₃ = 8.1 Hz, 2 H) BB-25-2 Carbonic acid Preparedaccording 0.95 (II) no io 5.18 (d, J = 8.7 pentafluorophenyl ester toMed. Chem. Hz, 2 H), 4.87 (d, 3-trifluoromethyl-oxetan- Commun., 2013,4, J = 9.6 Hz, 2 H) 3-yl ester 95-100 BB-25-3 Carbonic acid 3-methyl- A0.90 (II) no io 4.77 (d, J = 7.7 Hz, oxetan-3-yl ester3-Methyloxetan-3-ol 2 H), 4.54 (d, pentafluorophenyl ester J = 8.2 Hz, 2H), 1.76 (s, 3 H) BB-25-4 5-Isopropyl-3H- B 0.49 (II) 130.49 12.05 (sbr, 1 H), [1,3,4]oxadiazol-2-one Isobutyric acid 2.81-2.91 (m, 1 H),hydrazide 1.19 (d, J = 6.9 Hz, 6 H)

Synthesis of Building Blocks BB-26 Method A (SEM Protection)

To a suspension of the appropriate ketone (1 eq) and SEM-Cl (1.3 eq) inDCM (3.5 mL/mmol) was added dropwise DIPEA (1.5 eq) at 0° C. The rxnmixture was stirred at 0° C. for 1.5 h and quenched with a sat. aq.soln. of NaHCO₃. It was extracted with DCM, the org. phase was washedwith a sat. aq. soln. of NaHCO₃, dried over MgSO₄ and concentrated invacuo. The crude was purified by CC using Hept/EtOAc.

Method B (THP Protection)

To a suspension of the appropriate ketone (1 eq) in DCM (1.6 mL/mmol)was added TsOH (0.1 eq) and 3,4-dihydro-2H-pyran (1.3 eq). The rxnmixture was stirred at RT for 1.5 h and quenched with a sat. aq. soln.of NaHCO₃. It was extracted with DCM, the org. phase was washed with asat. aq. soln. of NaHCO₃ and brine, dried over MgSO₄ and concentrated invacuo. The crude was purified by CC using Hept/EtOAc.

TABLE 25 Method t_(R) [min] MS-data ¹H NMR Reactant (LC/MS m/z (500 MHz,BB-26 Name ketone method) [M + H]⁺ DMSO-d6) δ: BB-26-11-(1-Methyl-4-nitro-1H- commercially available pyrazol-3-yl)-ethanoneBB-26-2 1-[4-Nitro-2-(2- A 1.05 (I) no io 8.41 (s, 1 H), 5.48trimethylsilanyl- 1-(4-Nitro-1H- (s, 2 H), 3.55 (m, 2 H),ethoxymethyl)-2H- pyrazol-5- 2.65 (s, 3 H), 0.85 pyrazol-3-yl]-ethanoneyl)ethanone (m, 2 H), −0.03 (m, 9 H) BB-26-3 1-[4-Nitro-1-(2- 1.01 (I)286.25 trimethylsilanyl- ethoxymethyl)-1H- pyrazol-3-yl]-ethanoneBB-26-4 1-[4-Nitro-1-(tetrahydro- B 0.80 (I) 240.22pyran-2-yl)-1H-pyrazol- 1-(4-Nitro-1H- 3-yl]-ethanone pyrazol-5-yl)ethanone

Building Blocks BB-28

TABLE 26 BB-28 Name BB-28-1 3-Amino-1-methyl-1H- commerciallypyrazole-4-carbonitrile available

Synthesis of Building Blocks BB-29

To a mixture of the appropriate amine E (1 eq), the appropriate halide(1.05 to 1.2 eq) and sodium tert-butoxide (2 eq) in toluene (3 mL/mmol)under N₂, was added BINAP (0.2 eq) and Pd₂(dba)₃ (0.1 eq). The rxnmixture was flushed with N₂, heated to a given temperature in a sealedvial and stirred for a given time (see Table 27). It was partitionedbetween water and EtOAc and the org. phase was washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc.

TABLE 27 T [° C.] t_(R) [min] MS-data Reactant Reactant time (LC/MS m/zBB-29 Name amine E halide [h] method) [M + H]⁺ BB-29-18-(2-Fluoro-6-methyl- 1,4-Dioxa-8- 2-Bromo-3- 100    1.01 (I) 252.19phenyl)-1,4-dioxa-8- azaspiro[4.5]decane fluorotoluene 18  aza-spiro[4.5]decane BB-29-2 8-(2-Methoxy-4-methyl- 1,4-Dioxa-8-3-Bromo-2- 100    0.81 (I) 265.19 pyridin-3-yl)-1,4-dioxa-azaspiro[4.5]decane methoxy-4- 20   8-aza-spiro[4.5]decanemethylpyridine BB-29-3 8-(2-Fluoro-6-methyl- 1,4-Dioxa-8- 2-Bromo-3-100    1.03 (I) 266.30 phenyl)-1,4-dioxa-8- azaspiro[4.6]undecanefluorotoluene 2.5 aza-spiro[4.6]undecane BB-29-4 7-(2-Fluoro-6-methyl-1,4-Dioxa-7- 2-Bromo-3- 100    1.00 (I) 252.29 phenyl)-1,4-dioxa-7-azaspiro[4.5]decane fluorotoluene 6   aza-spiro[4.5]decane BB-29-58-(2-Methoxy-4- 1,4-Dioxa-8- 3-Bromo-2- 100    1.03 (I) 319.16trifluoromethyl-pyridin- azaspiro[4.5]decane methoxy-4- 18  3-yl)-1,4-dioxa-8-aza- trifluoromethyl- spiro[4.5]decane pyridineBB-29-6 8-(4-Chloro-2-methoxy- 1,4-Dioxa-8- 3-Bromo-4- 80   0.96 (I)285.12 pyridin-3-yl)-1,4-dioxa- azaspiro[4.5]decane chloro-2- 6  8-aza-spiro[4.5]decane methoxy- pyridine

Synthesis of Building Blocks BB-30 Step A: Aromatic NucleophilicSubstitution

To a soln. of the appropriate amine F (1 eq) and the appropriate halide(1.1 eq) in a given solvent (0.9 to 1.5 mL/mmol) was added K₂CO₃ (2 eq)and the mixture was heated to a given temperature and stirred for 18 h(see Table 28). It was quenched with water and extracted with DCM orEtOAc. The org. phase was washed with water and brine, dried over MgSO₄and concentrated in vacuo. The crude was purified by CC using Hept/EtOAcor DCM/MeOH.

TABLE 28 t_(R) [min] MS-data Reactant Reactant Solvent (LC/MS m/z BB-30AName amine F halide T [° C.] method) [M + H]⁺ BB-30-1A[1-(2-Fluoro-6-formyl- 4-(Boc-amino) 2,3-Difluoro- DMSO  0.93 (II)323.20 phenyl)-piperidin-4-yl]- piperidine benzaldehyde 100 carbamicacid tert-butyl ester BB-30-2A [1-(2-Fluoro-6-formyl- 4-(Boc-2,3-Difluoro- DMA 1.05 (I) 337.15 phenyl)-4-methyl-piperidin-4-amino)-4- benzaldehyde 120 yl]-carbamic acid methyl- tert-butyl esterpiperidine BB-30-3A [1-(2-Fluoro-6-formyl- 3-(Boc- 2,3-Difluoro- DMA1.03 (I) 323.17 phenyl)-3-methyl-pyrrolidin- amino)-3- benzaldehyde 1203-yl]-carbamic acid tert-butyl methyl- ester pyrrolidine BB-30-4A[(R)-1-(2-Fluoro-6-formyl- (R)-3-(Boc- 2,3-Difluoro- DMSO 0.98 (I)309.19 phenyl)-pyrrolidin-3-yl]- amino)pyrrolidine benzaldehyde 100carbamic acid tert-butyl ester BB-30-6A [1-(2-Fluoro-6-nitro-phenyl)-4-(Boc-amino) 2,3-Difluoro- DMA 1.05 (I) 340.22 piperidin-4-yl]-carbamicacid piperidine nitrobenzene  80 tert-butyl ester BB-30-7A(4′-Formyl-2′-methoxy- 4-(Boc-amino) 3-fluoro-2- DMA 0.95 (I) 336.213,4,5,6-tetrahydro-2H- piperidine methoxypyridine- 120[1,3′]bipyridinyl-4-yl)- 4-carbaldehyde carbamic acid tert-butyl ester

Step B Method A: Reduction

A suspension of intermediate BB-30A (1 eq) in anh. MeOH (2 mL/mmol) wascooled to 0° C. and NaBH₄ (1.2 to 1.3 eq) was added portionwise at 0° C.(see Table 29). The rxn mixture was stirred for 1 h at 0° C. to reachcompletion. It was carefully quenched by dropwise addition of water at0° C. and extracted with EtOAc. The org. phase was washed with water andbrine, dried over MgSO₄ and concentrated in vacuo.

Method B: Hydrogenation

Intermediate BB-30A (1 eq) was dissolved in EtOH (5 mL/mmol). The flaskwas evacuated three times and refilled with nitrogen. Wet Pd/C (0.05 eq)was added and the flask was evacuated three times and refilled withhydrogen. The suspension was stirred under an atmospheric pressure ofhydrogen for 3 h and filtered over a pad of Celite. The cake was washedwith EtOAc and MeOH and the filtrate was concentrated in vacuo.

TABLE 29 Method t_(R) [min] MS-data Reactant (LC/MS m/z BB-30B NameBB-32A method) [M + H]⁺ BB-30-1B [1-(2-Fluoro-6-hydroxymethyl- A  0.82(II) 325.24 phenyl)-piperidin-4-yl]- BB-30-1A carbamic acid tert-butylester BB-30-2B [1-(2-Fluoro-6- A 0.86 (I) 339.23hydroxymethyl-phenyl)-4-methyl- BB-30-2A piperidin-4-yl]-carbamic acidtert-butyl ester BB-30-3B [1-(2-Fluoro-6-hydroxymethyl- A 0.82 (I)325.22 phenyl)-3-methyl-pyrrolidin-3- BB-30-3A yl]-carbamic acid tert-butyl ester BB-30-4B [(R)-1-(2-Fluoro-6- A 0.82 (I) 311.23hydroxymethyl-phenyl)- BB-30-4A pyrrolidin-3-yl]-carbamic acidtert-butyl ester BB-30-6B [1-(2-Amino-6-fluoro-phenyl)- B 0.88 (I)310.28 piperidin-4-yl]-carbamic BB-30-6A acid tert-butyl ester

Step C Method A: Acetylation

A soln. of intermediate BB-30B (1 eq) and TEA (1.5 eq) in DCM (0.5 to 5mL/mmol) was cooled to 0° C. and AcCl (1.5 eq) was added dropwise at 0°C. (see Table 30). The rxn mixture was stirred for 1 h at 0° C. to reachcompletion. It was diluted with DCM and washed with a 10% aq. soln. ofcitric acid, with a sat. aq. soln. of NaHCO₃ and with brine. The org.phase was dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc.

Method B: Sandmeyer Rxn (Bromination)

To a soln. of intermediate BB-30B (1 eq) in MeCN (5 mL/mmol) was addeddropwise at 0° C. tetrafluoroboric acid as diethyl ether complex (1.2eq). The soln. was stirred for 5 min at 0° C. and tert-butyl nitrite(1.2 eq) was added dropwise. The rxn mixture was added dropwise at 0° C.to a suspension of copper(I) bromide (1.5 eq) and copper(II) bromide (3eq) in H₂O (3.1 mL/mmol). The resulting soln. was stirred for 18 hallowing the temperature to reach RT. It was partitioned between EtOAcand a sat. soln. of NHaCl. The org. phase was washed with a sat. soln.of NHaCl and brine, dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using Hept/EtOAc.

TABLE 30 Method t_(R) [min] MS-data Reactant (LC/MS m/z BB-30C NameBB-30B method) [M + H]⁺ BB-30-1C Acetic acid 2-(4-tert- A  0.97 (II)367.25 butoxycarbonylamino- BB-30-1B piperidin-1-yl)-3- fluoro-benzylester BB-30-2C Acetic acid 2-(4-tert- A 1.09 (I) 381.22butoxycarbonylamino-4- BB-30-2B methyl-piperidin-1-yl)- 3-fluoro-benzylester BB-30-3C Acetic acid 2-(3-tert- A 1.06 (I) 367.22butoxycarbonylamino-3- BB-30-3B methyl-pyrrolidin-1-yl)- 3-fluoro-benzylester BB-30-4C Acetic acid 2-((R)-3-tert- A 1.02 (I) 353.14butoxycarbonylamino- BB-30-4B pyrrolidin-1-yl)-3- fluoro-benzyl esterBB-30-6C [1-(2-Bromo-6-fluoro- B 1.13 (I) 373.15phenyl)-piperidin-4-yl]- BB-30-6B carbamic acid tert- butyl ester

Final Step

Method A: hydrogenation (using BB-30C) Intermediate BB-300 (1 eq) wasdissolved in a mixture of MeOH (6 mL/mmol) and EtOAc (2 mL/mmol) and theflask was evacuated three times and refilled with nitrogen (see Table31). Wet Pd/C (0.08 eq) was added and the flask was evacuated threetimes and refilled with hydrogen. The suspension was hydrogenated underatmospheric pressure for 3 h and filtered over a pad of Celite. The cakewas washed with EtOAc and MeOH and the filtrate was concentrated invacuo. The crude was purified by CC using Hept/EtOAc.

Method B: Fluorination (Using BB-30A)

To a soln. of intermediate BB-30A (1 eq) in DCM (6 to 58 mL/mmol) wasadded dropwise a 50% soln. of bis(2-methoxyethyl)aminosulfur trifluoride(2 to 2.75 eq). The soln. was stirred for 4 to 18 h at RT (see Table31), quenched at 0° C. with a sat. aq. soln. of NaHCO₃ and extractedwith DCM. The org. phase was dried over MgSO₄ and concentrated in vacuo.The crude was purified by CC using Hept/EtOAc.

Method C: Sandmeyer Rxn (Chlorination Using BB-30B)

To a soln. of intermediate BB-30B (1 eq) in MeCN (5 mL/mmol) was addeddropwise at 0° C. tetrafluoroboric acid as diethyl ether complex (1.2eq). The soln. was stirred for 5 min at 0° C. and tert-butyl nitrite(1.2 eq) was added dropwise.

The rxn mixture was added dropwise at 0° C. to a suspension of copper(I)chloride (1.5 eq) and copper(II) chloride (3 eq) in H₂O (3.1 mL/mmol).The resulting soln. was stirred for 18 h allowing the temperature toreach RT. It was partitioned between EtOAc and a sat. soln. of NH₄Cl.The org. phase was washed with a sat. soln. of NH₄Cl and brine, driedover MgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc.

Method D: Kumada Rxn (Using BB-30C)

To a mixture of intermediate BB-30 (1 eq) anddi-p-iodobis(tri-t-butylphosphino)dipalladium( ) in toluene (3.8mL/mmol) was added dropwise under argon a 1 M soln. ofcyclopropylmagnesium bromide in 2-methyl tetrahydrofuran (4 eq). The rxnmixture was stirred at RT for a given time (see Table 31). Whennecessary, an extra amount of a 1M soln. of cyclopropylmagnesium bromidein 2-methyltetrahydrofuran (2 eq) was added. The rxn mixture wasquenched with H₂O and extracted with EtOAc. The org. phase was washedwith H₂O and brine, dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using Hept/EtOAc and when necessary, anadditional purification by prep. LC-MS using method 1 was performed.

TABLE 31 Method Reactant t_(R) [min] MS-data BB-30C, BB-30- (LC/MS m/zBB-30 Name B or BB-30A method) [M + H]⁺ BB-30-1 [1-(2-Fluoro-6-methyl- A 1.00 (II) 309.16 phenyl)-piperidin-4-yl]- BB-30-1C carbamic acidtert-butyl ester BB-30-2 [1-(2-Fluoro-6-methyl- A 1.12 (I) 323.24phenyl)-4-methyl- BB-30-2C piperidin-4-yl]- carbamic acid tert-butylester BB-30-3 [1-(2-Fluoro-6-methyl- A 1.02 (I) 309.24 phenyl)-3-methyl-BB-30-3C pyrrolidin-3-yl]- carbamic acid tert-butyl ester BB-30-4[(R)-1-(2-Fluoro-6-methyl- A 0.99 (I) 295.29 phenyl)-pyrrolidin-3-yl]-BB-30-4C carbamic acid tert-butyl ester BB-30-6 [1-(2-Difluoromethyl-6-B 1.09 (I) 345.43 fluoro-phenyl)-piperidin-4-yl]- BB-30-1A carbamic acidtert-butyl ester BB-30-7 [1-(2-Chloro-6-fluoro- C 1.10 (I) 329.16phenyl)-piperidin-4-yl]- BB-30-6B carbamic acid tert-butyl ester BB-30-8[1-(2-Cyclopropyl-6-fluoro- D 1.14 (I) 335.26 phenyl)-piperidin-4-yl]-BB-30-6C carbamic acid tert-butyl ester BB-30-9 (4′-Difluoromethyl-2′- B1.09 (I) 358.21 methoxy-3,4,5,6-tetrahydro- BB-30-7A2H-[1,3′]bipyridinyl-4-yl)- carbamic acid tert-butyl ester

Synthesis of Building Blocks BB-31

To a mixture of the appropriate amine G (1 eq), the appropriate halide(1.5 eq) and sodium tert-butoxide (2 eq) in toluene (3.5 mL/mmol) underN₂, was added BINAP (0.2 eq) and Pd₂(dba)₃ (0.1 eq) (see Table 32). Therxn mixture was flushed with N₂, heated to 110° C. in a sealed vial andstirred for 1 h. It was partitioned between water and DM and the org.phase was washed with brine, dried over MgSO₄ and concentrated in vacuo.The crude was purified by CC using Hept/EtOAc.

TABLE 32 t_(R) [min] MS-data Reactant Reactant (LC/MS m/z BB-31 Nameamine G halide method) [M + H]⁺ BB-31-1 3-(tert-Butyl-dimethyl-3-[(tert-Butyl 2-Bromo-3- 1.21 (I) 296.28 silanyloxy)-1-(2-fluoro-dimethylsilanyl)oxy] fluorotoluene 6-methyl-phenyl)-azetidine azetidine

Synthesis of Building Blocks BB-32

To a soln. of intermediate BB-31 (1 eq) in THE (3 mL/mmol) was addeddropwise at 0° C. a 1 M soln. of TBAF (2 eq) in THF. The rxn mixture wasstirred for 30 min at 0° C. (see Table 33) and partitioned between DCMand water. The org. phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC using DCM/MeOH.

TABLE 33 t_(R) [min] MS-data Reactant (LC/MS m/z BB-32 Name BB-31method) [M + H]⁺ BB-32-1 1-(2-Fluoro-6- BB-31-1 0.60 (I) 182.35methyl-phenyl)- azetidin-3-ol

Synthesis of Building Blocks BB-33

To a soln. of intermediate BB-32 (1 eq), TEA (2 eq) and catalytic amountof DMAP (0.25 eq) in DCM (5 mL/mmol) was added at 0° C.p-toluenesulfonyl chloride (1.3 eq). The rxn mixture was allowed to warmto RT and stirred for 2 h (see Table 34). When necessary to reachcompletion of the rxn, an extra amount of p-toluenesulfonyl chloride(0.3 eq) was added. It was partitioned between water and DCM and theorg. phase was washed with brine, dried over MgSO₄ and concentrated invacuo. The crude was purified by CC using DCM.

TABLE 34 t_(R) [min] MS-data Reactant (LC/MS m/z BB-33 Name BB-32method) [M + H]⁺ BB-33-1 Toluene-4-sulfonic acid BB-32-2 1.08 (I) 336.151-(2-fluoro-6-methyl- phenyl)-azetidin-3-yl ester

Building Blocks BB-34

BB-34 Name BB-34-1 3-amino-4-bromopyrazole commercially BB-34-24-Bromo-1-methyl-1H-pyrazol-3-ylamine available

Synthesis of Intermediates of Formula A-1 Method A (NaBH(OAc)₃/THF)

To a soln. of aldehyde BB-4 (1 eq) and amine BB-7 (1 to 1.15 eq) in THE(4 to 8 mL/mmol) were added AcOH (1.5 eq) and the rxn mixture wasstirred for 20 min at RT. NaBH(OAc)₃ (1.5 eq) was added portionwise andthe rxn mixture was stirred at RT for a given time (see Table 35). Whennecessary to reach completion of the rxn, an extra portion of NaBH(OAc)₃(1 eq) was added at RT. It was partitioned between EtOAc and a sat. aq.soln. of NaHCO₃. The org. phase was washed with brine, dried over MgSO₄and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc/MeOH.

Method B (NaBH₄/TFE)

A soln. of aldehyde BB-4 (1 eq) and amine BB-7 (1 to 1.1 eq) in TFE (2mL/mmol) was stirred for 10 min at 40° C. and cooled to 0° C. NaBH₄ (1.2eq) was added portionwise and the rxn mixture was stirred at 40° C. fora given time (see Table 35). It was quenched with a sat. aq. soln. ofNaHCO₃ and extracted with EtOAc. The combined org. phases were washedwith brine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc.

TABLE 35 t_(R) [min] MS-data Reactant Reactant Method (LC/MS m/z A-1Name BB-4 BB-7 time [h] method) [M + H]⁺ A-1-1A[1-(2-Fluoro-6-methyl-phenyl)- BB-4-1A BB-7-1 A 0.95 (I) 464.26piperidin-4-yl]-[4-nitro-2-(2- 18 trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-ylmethyl]-amine A-1-1B [1-(2-Fluoro-6-methyl-phenyl)-BB-4-1B BB-7-1 A 0.93 (I) 464.29 piperidin-4-yl]-[4-nitro-1-(2- 18trimethylsilanyl-ethoxymethyl)- 1H-pyrazol-3-ylmethyl]-amine A-1-2[1-(2-Fluoro-6-methyl-phenyl)- BB-4-2 BB-7-1 A 0.94 (I) 464.25piperidin-4-yl]-[3-nitro-1-(2-  2 trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylmethyl]-amine A-1-3 [1-(2-Fluoro-6-methyl-phenyl)- BB-4-3BB-7-1 A  0.69 (II) 348.21 piperidin-4-yl]-(1-methyl-4-nitro-  11H-pyrazol-3-ylmethyl)-amine A-1-4 [1-(2-Fluoro-6-methyl-phenyl)- BB-4-4BB-7-1 B  0.85 (II) 464.22 piperidin-4-yl]-[5-nitro-3-(2-  1trimethylsilanyl-ethoxymethyl)- 3H-imidazol-4-ylmethyl]-amine A-1-5(2′-Methoxy-4′-methyl-3,4,5,6- BB-4-2 BB-7-2 A 0.93 (I) 477.23tetrahydro-2H-[1,3′]bipyridinyl-4- 24yl)-[3-nitro-1-(2-trimethylsilanyl- ethoxymethyl)-1H-pyrazol-4-ylmethyl]-amine A-1-6 (2′-Methoxy-4′-methyl-3,4,5,6- BB-4-1A BB-7-2 A0.93 (I) 477.25 tetrahydro-2H-[1,3′]bipyridinyl-4- 24yl)-[4-nitro-2-(2-trimethylsilanyl- ethoxymethyl)-2H-pyrazol-3-ylmethyl]-amine A-1-7 [1-(2-Fluoro-6-methyl-phenyl)-4- BB-4-5 BB-7-3 A0.76 (I) 362.21 methyl-piperidin-4-yl]-(1-methyl- 183-nitro-1H-pyrazol-4-ylmethyl)- amine A-1-8[1-(2-Fluoro-6-methyl-phenyl)-3- BB-4-5 BB-7-4 A 0.77 (I) 348.21methyl-pyrrolidin-3-yl]-(1-methyl- 18 3-nitro-1H-pyrazol-4-ylmethyl)-amine

Synthesis of Intermediates of Formula A-2 Method A (Nitro Reduction fromA-1)

To a soln. of intermediate A-1 (1 eq) in EtOH (3.5 to 7.4 mL/mmol) wasadded 10% Pd/C moistened with ˜50% water (0.02 eq) and the rxn mixturewas hydrogenated under atmospheric pressure for a given time (see Table36). It was filtered over a pad of celite and the filtrate wasconcentrated in vacuo. When necessary, the crude was purified by CCusing Hept/EtOAc or DCM/MeOH.

Method B1 (Reductive Amination from BB-5 and BB-8 Using NaBH(OAc)₃)

To a soln. of amine BB-5 (1 eq) and ketone BB-8 (1.05 to 1.2 eq) in THE(4 mL/mmol) was added AcOH (1.5 eq) and the rxn mixture was stirred for5 min at RT. NaBH(OAc)₃ (1.5 eq) was added portionwise and the rxnmixture was stirred at RT for a given time (see Table 36). It wasacidified with a 1M aq. soln. of HCl until pH˜3-4 and extracted withDCM. The aq. phase was basified with a sat. aq. soln. of NaHCO₃ andextracted with DCM. The combined org. phases were dried over MgSO₄ andconcentrated in vacuo. When necessary, the crude was purified by CCusing Hept/EtOAc/MeOH.

Method B2 (Reductive Amination from BB-5 and BB-8 Using NaBH₄)

A soln. of amine BB-5 (1 eq) and ketone BB-8 (1.05 eq) in MeOH (4mL/mmol) was stirred for 18 h at RT. NaBH₄ (1.6 eq) was addedportionwise at 0° C. and the rxn mixture was stirred at RT for a giventime (see Table 36). It was quenched with H₂O at 0° C., basified with a1M aq. soln. of NaOH and extracted with DCM. The combined org. phaseswere dried over MgSO₄ and concentrated in vacuo. When necessary, thecrude was purified by CC using EtOAc/MeOH.

Method C (Reductive Amination from BB-6 and BB-7)

To a soln. of aldehyde BB-6 (1 eq) and amine BB-7 (1.1 eq) in THE (4mL/mmol) was added AcOH (1.5 eq) and the rxn mixture was stirred for 5min at RT. NaBH(OAc)₃ (1.5 eq) was added portionwise and the rxn mixturewas stirred at RT for a given time (see Table 36). It was acidified witha 10% aq. soln. of citric acid and extracted with DCM. The aq. phase wasbasified with a 1M aq. soln. of NaOH and extracted with DCM. Thecombined org. phases were dried over MgSO₄ and concentrated in vacuo.When necessary, the crude was purified by prep. LC-MS using method 7.

Method D (Reductive Amination from BB-7 and BB-20)

A soln. of aldehyde BB-20 (1 eq) in TFE (2 mL/mmol) was stirred at 35°C. for 5 min. Amine BB-7 (1 eq) was added and the rxn mixture stirred at35° C. for 5 min. NaBH₄ (1.2 eq) was added portionwise and the rxnmixture was stirred at 3500 for a given time (see Table 36). It wasquenched with H₂O, basified with a 1 M aq. soln. of NaOH and extractedwith DCM. The combined org. phases were dried over MgSO₄ andconcentrated in vacuo.

Method E (Boc cleavage from A-4)

To a Soln. Of Intermediate A-4 (1 Eq) in DCM (5 mL/Mmol) was Added TFA(1.5 to 2 mL/Mmol) at 0° C. and the Rxn mixture was stirred at RT for agiven time (see Table 36). It was cooled to 0° C., quenched with a 1Maq. soln. of NaOH until pH reached 12 to 13 and extracted with DCM. Thecombined org. phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo.

Method F (Nucleophilic Substitution of BB-5 on BB-33)

A soln. of intermediate BB-33 (1 eq) and amine BB-5 (3 eq) in MeCN (5.7mL/mmol) was heated at 110° C. under microwave irradiation for a giventime (see Table 36) and filtered. The filtrate was purified by prep.LC-MS using method 12.

TABLE 36 Reactant Reactant Method A-1, BB-5, BB-8, T [° C.] t_(R) [min]MS-data BB-6, BB-20 BB-7 or time (LC/MS m/z A-2 Name or A-4 BB-33 [h]method) [M + H]⁺ A-2-1A [4-Amino-2-(2-trimethylsilanyl- A-1-1A — A 0.85(I) 433.86 ethoxymethyl)-2H-pyrazol-3- RTylmethyl]-[1-(2-fluoro-6-methyl- 3   phenyl)-piperidin-4-yl]-amineA-2-1B [4-Amino-1-(2-trimethylsilanyl- A-1-1B — A 0.81 (I) 433.80ethoxymethyl)-1H-pyrazol-3- RT ylmethyl]-[1-(2-fluoro-6-methyl- 2  phenyl)-piperidin-4-yl]-amine A-2-2 [3-Amino-1-(2-trimethylsilanyl-A-1-2 — A 0.85 (I) 434.10 ethoxymethyl)-1H-pyrazol-4- RTylmethyl]-[1-(2-fluoro-6-methyl- 18   phenyl)-piperidin-4-yl]-amineA-2-3 (4-Amino-1-methyl-1H-pyrazol- A-1-3 — A  0.56 (II) 318.133-ylmethyl)-[1-(2-fluoro-6- RT methyl-phenyl)-piperidin-4-yl]- 2   amineA-2-4 [5-Amino-3-(2-trimethylsilanyl- A-1-4 — A  0.72 (II) 434.23ethoxymethyl)-3H-imidazol-4- (EtOAc ylmethyl]-[1-(2-fluoro-6-methyl-replacing phenyl)-piperidin-4-yl]-amine EtOH) RT 1.5 A-2-5(3-Amino-1-methyl-1H-pyrazol- BB-5-1 BB-8-1 B  0.61 (II) 318.134-ylmethyl)-[1-(2-fluoro-6- RT methyl-phenyl)-piperidin-4-yl]- 0.5 amineA-2-6 4-{[(R)-1-(2-Fluoro-6-methyl- BB-6-1 BB-7-5 C  0.60 (II) 304.12phenyl)-pyrrolidin-3-ylamino]- RT methyl}-1-methyl-1H-pyrazol- 2.53-ylamine A-2-7 (5-Amino-1-benzyl-1H- BB-5-2 BB-8-1 B  0.71 (II) 395.21[1,2,3]triazol-4-ylmethyl)-[1- RT (2-fluoro-6-methyl-phenyl)- 18  piperidin-4-yl]-amine A-2-8 (5-Amino-2-methyl-thiazol-4- BB-20-1 BB-7-1D  0.67 (II) 335.11 ylmethyl)-[1-(2-fluoro-6-methyl- 35  phenyl)-piperidin-4-yl]-amine 18   A-2-9 (5-Amino-2-methyl-2H- A-4-1 — E 0.65 (II) 319.17 [1,2,3]triazol-4-ylmethyl)-[1-(2- RTfluoro-6-methyl-phenyl)- 3   piperidin-4-yl]-amine A-2-10(3-Amino-1-methyl-1H-pyrazol- BB-5-1 BB-8-2 B 0.53 (I) 331.244-ylmethyl)-(2′-methoxy-4′- RT methyl-3,4,5,6-tetrahydro-2H- 1  [1,3′]bipyridinyl-4-yl)-amine A-2-11 (5-Amino-2-methyl-2H- A-4-2 — E0.57 (I) 332.17 [1,2,3]triazol-4-ylmethyl)-(2′- RTmethoxy-4′-methyl-3,4,5,6- 4   tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-amine A-2-12 [3-Amino-1-(2-trimethylsilanyl- A-1-5 — A 0.79 (I)447.31 ethoxymethyl)-1H-pyrazol-4- RT ylmethyl]-(2′-methoxy-4′- 5  methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine A-2-13[4-Amino-2-(2-trimethylsilanyl- A-1-6 — A 0.80 (I) 447.30ethoxymethyl)-2H-pyrazol-3- RT ylmethyl]-(2′-methoxy-4′- 2.5methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine A-2-14(3-Amino-1-methyl-1H-pyrazol- A-1-7 — A 0.67 (I) 332.274-ylmethyl)-[1-(2-fluoro-6- RT methyl-phenyl)-4-methyl- 4  piperidin-4-yl]-amine A-2-15 (3-Amino-1-methyl-1H-pyrazol- BB-5-1 BB-8-3B 0.69 (I) 332.25 4-ylmethyl)-[1-(2-fluoro-6- RTmethyl-phenyl)-azepan-4-yl]- 18   amine A-2-16 4-{[1-(2-Fluoro-6-methyl-A-1-8 — A 0.66 (I) 318.22 phenyl)-3-methyl-pyrrolidin-3- RTylamino]-methyl}-1-methyl-1H- 2   pyrazol-3-ylamine A-2-17(3-Amino-1-methyl-1H-pyrazol- BB-5-1 BB-8-4 B 0.64 (I) 318.224-ylmethyl)-[1-(2-fluoro-6- RT methyl-phenyl)-piperidin-3-yl]- 20  amine A-2-18 4-{[1-(2-Fluoro-6-methyl- BB-5- BB-33-1 F 0.57 (I) 290.04phenyl)-azetidin-3-ylamino]- 110    methyl}-1-methyl-1H-pyrazol- 1  3-ylamine

Synthesis of Intermediates of Formula A-3 Method A1 (or A2,Respectively) (Cyclisation from A-2)

To a soln. of intermediate A-2 (1 eq) in MeCN (or DCM, respectively)(3.7 to 10 mL/mmol) was added CDI (or DSC, respectively) (1.2 to 2 eq)and the rxn mixture was stirred at a given temperature for a given time(see Table 37). When necessary to reach completion of the rxn an extraamount of CDI (0.5 to 1 eq) was added. The solvent was evaporated offand the residue was partitioned between EtOAc or DCM and water. The org.phase was washed with brine, dried over MgSO₄ and concentrated in vacuo.When necessary, the crude was purified by CC using Hept/EtOAc orDCM/MeOH, by precipitation from DCM/MeOH/Et₂O or MeCN or by prep. LC-MSusing method 12.

Method B (Cyclisation from D-1)

A soln. of intermediate D-1 (1 eq) in DMF (8 mL/mmol) was heated at 120°C. under microwave irradiation for a given time (see Table 37) andpartitioned between EtOAc and H₂O. The org. phase was washed with H₂Oand brine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc.

TABLE 37 Method t_(R) [min] MS-data Reactant T [° C.] (LC/MS m/z A-3Name A-2 or D-1 time [h] method) [M + H]⁺ A-3-1A6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-1A A1 1.15 (I) 460.16yl]-1-(2-trimethylsilanyl-ethoxymethyl)- RT1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 0.5 5-one A-3-1B6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-1B A1 1.13 (I) 460.28yl]-2-(2-trimethylsilanyl-ethoxymethyl)- RT2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 0.8 5-one A-3-25-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-2 A1 1.16 (I) 460.26yl]-2-(2-trimethylsilanyl-ethoxymethyl)- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 1.5 6-one A-3-36-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-3 A1  0.85 (II) 344.10yl]-2-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3- RT d]pyrimidin-5-one 18  A-3-4 1-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-4 A1  1.07 (II)460.24 yl]-7-(2-trimethylsilanyl-ethoxymethyl)- RT1,3,6,7-tetrahydro-purin-2-one 18   A-3-55-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-5 A1  0.93 (II) 344.18yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- RT d]pyrimidin-6-one 1.5A-3-6 5-[(R)-1-(2-Fluoro-6-methyl-phenyl)- A-2-6 A1  0.70 (II) 330.09pyrrolidin-3-yl]-2-methyl-2,4,5,7-tetrahydro- RTpyrazolo[3,4-d]pyrimidin-6-one 2   A-3-73-Benzyl-6-[1-(2-fluoro-6-methyl-phenyl)- A-2-7 A1 (THF  0.93 (II)421.13 piperidin-4-yl]-3,4,6,7-tetrahydro- replacing[1,2,3]triazolo[4,5-d]pyrimidin-5-one MeCN) 80   24   A-3-86-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- D-1-1 B  0.89 (II) 345.19yl]-2-methyl-6,7-dihydro-4H-oxazolo[5,4- 120    d]pyrimidin-5-one 0.13A-3-9 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-8 A1  0.90 (II)361.07 yl]-2-methyl-6,7-dihydro-4H-thiazolo[5,4- RT d]pyrimidin-5-one24   A-3-10 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-9 A1  0.89(II) 345.20 yl]-2-methyl-2,4,6,7-tetrahydro- RT[1,2,3]triazolo[4,5-d]pyrimidin-5-one 3.5 A-3-115-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-2-10 A1 0.83 (I) 357.212H-[1,3′]bipyridinyl-4-yl)-2-methyl-2,4,5,7- RTtetrahydro-pyrazolo[3,4-d]pyrimidin-6-one  0.25 A-3-126-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-2-11 A1 0.81 (I) 358.212H-[1,3′]bipyridinyl-4-yl)-2-methyl-2,4,6,7- RTtetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5- 18   one A-3-135-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-2-12 A1 1.06 (I) 473.292H-[1,3′]bipyridinyl-4-yl)-2-(2-trimethylsilanyl- RTethoxymethyl)-2,4,5,7-tetrahydro- 2   pyrazolo[3,4-d]pyrimidin-6-oneA-3-14 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-2-13 A1 1.06 (I)473.27 2H-[1,3′]bipyridinyl-4-yl)-1-(2-trimethylsilanyl- RTethoxymethyl)-1,4,6,7-tetrahydro- 1   pyrazolo[4,3-d]pyrimidin-5-oneA-3-15 5-[1-(2-Fluoro-6-methyl-phenyl)-4-methyl- A-2-14 A1 1.02 (I)358.22 piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro- RTpyrazolo[3,4-d]pyrimidin-6-one 18   A-3-165-[1-(2-Fluoro-6-methyl-phenyl)-azepan-4- A-2-15 A1 1.03 (I) 358.21yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- RT d]pyrimidin-6-one 2  A-3-17 5-[1-(2-Fluoro-6-methyl-phenyl)-3-methyl- A-2-16 A1 0.94 (I)344.18 pyrrolidin-3-yl]-2-methyl-2,4,5,7-tetrahydro- RTpyrazolo[3,4-d]pyrimidin-6-one 0.5 A-3-185-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-3- A-2-17 A1 0.99 (I) 344.16yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- RT d]pyrimidin-6-one 1  A-3-19 5-[1-(2-Fluoro-6-methyl-phenyl)-azetidin-3- A-2-18 A2 0.61 (I)316.17 yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 45  d]pyrimidin-6-one 18  

Synthesis of Intermediates of Formula A-4

To a soln. of amine BB-24 (1 eq) and ketone B-8 (1.1 to 1.2 eq) in THE(10 m-8 mmol) was added AcOH (1.5 eq) and the rxn mixture was stirredfor 5 min at RT. NaBH(OAc)₃ (1.5 eq) was added portionwise and the rxnmixture was stirred at RT for a given time (see Table 38). It wasquenched with a sat. aq. soln. of NaHCO₃ and extracted with DCM. Thecombined org. phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC usingHept/EtOAc/MeOH.

TABLE 38 t_(R) [min] MS-data Reactant Reactant time (LC/MS m/z A-4 NameBB-24 BB-8 [h] method) [M + H]⁺ A-4-1(5-{[1-(2-Fluoro-6-methyl-phenyl)-piperidin- BB-24-1 BB-8-1 2   0.80(II) 419.19 4-ylamino]-methyl]-2-methyl-2H-[1,2,3]triazol-4-yl)-carbamic acid tert-butyl ester A-4-2{5-[(2′-Methoxy-4′-methyl-3,4,5,6- BB-24-1 BB-8-2 1.5 0.78 (I) 432.29tetrahydro-2H-[1,3′]bipyridinyl-4-ylamino)-methyl]-2-methyl-2H-[1,2,3]triazol-4-yl}- carbamic acid tert-butyl ester

Synthesis of Intermediates of Formula B-1

To a suspension of intermediate A-2 (1 eq) in anh. THE (3 mL/mmol) wasadded TEA (3 eq). The rxn mixture was cooled to 0° C. and Boc₂O (1.1 eq)was added. It was stirred for 10 min at 0° C. and at RT for a given time(see Table 39) and was partitioned between EtOAc and water. The org.phase was washed with brine, dried over MgSO₄ and concentrated in vacuo.When necessary, the crude was purified by CC using DCM/MeOH orHept/EtOAc.

TABLE 39 T [° C.] t_(R) [min] MS-data Reactant time (LC/MS m/z B-1 NameA-2 [h] method) [M + H]⁺ B-1-1 (3-Amino-1-methyl-1H-pyrazol- A-2-5 RT0.91 (II) 418.08 4-ylmethyl)-[1-(2-fluoro- 186-methyl-phenyl)-piperidin-4-yl]- carbamic acid tert-butyl ester

Synthesis of Intermediates of Formula B-2 Method A (NaBH(OAc)₄/AcOH/THF)

To a soln. of amine B-1 (1 eq) and aldehyde BB-12 (1.2 eq) in THE (4 to5 mL/mmol) was added AcOH (1.5 eq) and the rxn mixture was stirred for 5min at RT. NaBH(OAc)₃ (1.5 to 2 eq) was added portionwise and the rxnmixture was stirred at RT for a given time (see Table 40). Whennecessary to reach completion of the rxn an extra amount of NaBH(OAc)₃(0.2 to 1 eq) was added. The rxn mixture was quenched with a sat. aq.soln. of NaHCO₃ and extracted with DCM. The combined org. phases werewashed with brine, dried over MgSO₄ and concentrated in vacuo. Whennecessary, the crude was purified by CC using Hept/EtOAc/MeOH.

Method B (NaBH₄/TFE)

A soln. of amine B-1 (1 eq) and aldehyde BB-12 (1 eq) in TFE (2 mL/mmol)was stirred for 10 min at 35° C. and cooled to 0° C. NaBH₄ (1.2 eq) wasadded portionwise and the rxn mixture was stirred for a given time at agiven temperature (see Table 40). When necessary to reach completion ofthe rxn an extra amount of aldehyde BB-12 (1 eq) was added. It wasquenched with a sat. aq. soln. of NaHCO₃ and extracted with DCM. Thecombined org. phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

TABLE 40 Method T [° C.] t_(R) [min] MS-data Reactant Reactant time(LC/MS m/z B-2 Name B-1 BB-12 [h] method) [M + H]⁺ B-2-1[1-(2-Fluoro-6-methyl-phenyl)- B-1-1 BB-12-1 A 1.03 (II) 577.03piperidin-4-yl]-{1-methyl-3-[(3- RT trifluoromethyl-pyridin-2- 48ylmethyl)-amino]-1H-pyrazol-4- ylmethyl}-carbamic acid tert- butyl esterB-2-2 {3-[(6-Chloro-3-trifluoromethyl- B-1-1 BB-12-2 A 1.08 (II) 611.06pyridin-2-ylmethyl)-amino]-1- RT methyl-1H-pyrazol-4-ylmethyl}- 48[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-carbamic acid tert-butylester B-2-3 [1-(2-Fluoro-6-methyl-phenyl)- B-1-1 BB-12-3 B 1.09 (II)594.02 piperidin-4-yl]-[3-(2-fluoro-6- 35trifluoromethyl-benzylamino)-1-  4 methyl-1H-pyrazol-4-ylmethyl]-carbamic acid tert-butyl ester

Synthesis of Intermediates of Formula B-3

To a soln. of intermediate B-2 (1 eq) in DCM (4 to 16.5 mL/mmol) wasadded TFA (1 to 3.2 mL/mmol) and the rxn mixture was stirred at RT for agiven time (see Table 41). It was quenched with a 2M aq. soln. of NaOHuntil pH 12-13 and extracted with DCM. The combined org. phases werewashed with brine, dried over MgSO₄ and concentrated in vacuo. Whennecessary, the crude was purified by CC using DCM/MeOH.

TABLE 41 T [° C.] t_(R) [min] MS-data Reactant time (LC/MS m/z B-3 NameB-2 [h] method) [M + H]⁺ B-3-1[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]- B-2-1 RT 0.77 (II) 477.10{1-methyl-3-[(3-trifluoromethyl-pyridin-2- 4  ylmethyl)-amino]-1H-pyrazol-4-ylmethyl}-amine B-3-2{3-[(6-Chloro-3-trifluoromethyl-pyridin-2- B-2-2 RT 0.82 (II) 511.08ylmethyl)-amino]-1-methyl-1H-pyrazol-4- 3.5ylmethyl}-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-amine B-3-3[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]- B-2-3 RT 0.82 (II) 494.10[3-(2-fluoro-6-trifluoromethyl-benzylamino)-1- 1  methyl-1H-pyrazol-4-ylmethyl]-amine

Synthesis of Intermediates of Formula C-1 Method A (NaBH(OAc)₄/AcOH/THF)

To a soln. of amine BB-5 (1 eq) and ketone BB-13 (1.1 to 1.2 eq) in THE(4 mL/mmol) was added AcOH (1.5 eq) and the rxn mixture was stirred for5 min at RT. NaBH(OAc)₃ (1.5 eq) was added portionwise and the rxnmixture was stirred at RT for a given time (see Table 42). It wasquenched with a 1M aq. soln. of NaOH until pH 10 and extracted with DCM.The combined org. phases were dried over MgSO₄ and concentrated invacuo. When necessary, the crude was purified by CC using EtOAc/MeOH.

Method B (NaBH₄/TFE)

A soln. of aldehyde BB-14 (1 eq) and amine BB-15 (1.1 eq) in TFE (2mL/mmol) was stirred for 5 min at 40° C. and cooled to 0° C. NaBH₄ (1.2eq) was added portionwise and the rxn mixture was stirred for a giventime at a given temperature (see Table 42). It was quenched with a sat.aq. soln. of NaHCO₃ and extracted with DCM. The combined org. phaseswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Whennecessary, the crude was purified by CC using Hept/EtOAc.

Method C (Nitro Reduction from C-4)

To a soln. of intermediate C-4 (1 eq) in EtOH (4.5 mL/mmol) was added10% Pd/C moistened with ˜50% water (0.02 eq) and the rxn mixture washydrogenated under atmospheric pressure for a given time (see Table 42).It was filtered over a pad of celite and the filtrate was concentratedin vacuo.

TABLE 42 Method Reactant Reactant T [° C.] t_(R) [min] MS-data BB-5 orBB-13 or time (LC/MS m/z C-1 Name BB-14 BB-15 [h] method) [M + H]⁺ C-1-13-[(3-Amino-1-methyl-1H- BB-5-1 BB-13-1 A 0.49 (II) 296.16pyrazol-4-ylmethyl)-amino]- RT pyrrolidine-1-carboxylic acid tert- 18  butyl ester C-1-2 4-[(3-Amino-1-methyl-1H- BB-5-1 BB-13-2 A 0.51 (II)310.13 pyrazol-4-ylmethyl)-amino]- RT piperidine-1-carboxylic acid tert-1   butyl ester C-1-3 4-[(3-Amino-1-methyl-1H- BB-14-1 BB-15-1 B 0.53(II) 324.19 pyrazol-4-ylmethyl)-amino]- 40   azepane-1-carboxylic acidtert- 1   butyl ester C-1-4 4-[(4-Amino-1-methyl-1H- C-4-1 C 0.48 (I) 310.28 pyrazol-3-ylmethyl)-amino]- RT piperidine-1-carboxylic acid tert-4.5 butyl ester

Synthesis of Intermediates of Formula C-2

To a soln. of intermediate C-1 (1 eq) in MeCN (3.7 mL/mmol) was addedCDI (1.2 to 2 eq) and the rxn mixture was stirred at a given temperaturefor a given time (see Table 43). The solvent was evaporated off and theresidue was partitioned between DCM and water. The org. phase was washedwith brine, dried over MgSO₄ and concentrated in vacuo. When necessary,the crude was purified by CC using Hept/EtOAc or triturated in MeCN andthe solid was filtered.

TABLE 43 T [° C.] t_(R) [min] MS-data Reactant time (LC/MS m/z C-2 NameC-1 [h] method) [M + H]⁺ C-2-1 3-(2-Methyl-6-oxo-2,4,6,7-tetrahydro-C-1-1 RT 0.73 (II) 321.98 pyrazolo[3,4-d]pyrimidin-5-yl)-pyrrolidine-1-0.5 carboxylic acid tert-butyl ester C-2-24-(2-Methyl-6-oxo-2,4,6,7-tetrahydro- C-1-2 RT 0.75 (II) 336.14pyrazolo[3,4-d]pyrimidin-5-yl)-piperidine-1- 0.7 carboxylic acidtert-butyl ester C-2-3 4-(2-Methyl-6-oxo-2,4,6,7-tetrahydro- C-1-3 RT0.77 (II) 350.24 pyrazolo[3,4-d]pyrimidin-5-yl)-azepane-1- 18  carboxylic acid tert-butyl ester C-2-44-(2-Methyl-5-oxo-2,4,5,7-tetrahydro- C-1-4 RT 0.75 (I)  336.38pyrazolo[4,3-d]pyrimidin-6-yl)-piperidine-1- 0.5 carboxylic acidtert-butyl ester

Synthesis of Intermediates of Formula C-3

To a soln. of intermediate Ii (1 eq) in DCM (4 to 10 mL/mmol) was addedTFA (i to 1.6 mL/mmol) at 0° C. and the rxn mixture was stirred at RTfor a given time (see Table 44). It was cooled to 0° C., quenched with a32% aq. soln. of NaOH until pH reached 12 to 13 and extracted with DCM.The combined org. phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo.

TABLE 44 T [° C.] t_(R) [min] MS-data Reactant time (LC/MS m/z C-3 NameIi [h] method) [M + H]⁺ C-3-12-Methyl-5-pyrrolidin-3-yl-7-(2-trifluoromethyl- Ii-1 RT 0.64 (II)380.17 benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 18   d]pyrimidin-6-oneC-3-2 2-Methyl-5-piperidin-4-yl-7-(2-trifluoromethyl- Ii-2 RT 0.62 (II)394.08 benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-  0.75 d]pyrimidin-6-oneC-3-3 5-Azepan-4-yl-2-methyl-7-(2-trifluoromethyl- Ii-3 RT 0.64 (II)408.22 benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 0.5 d]pyrimidin-6-oneC-3-4 2-Methyl-6-piperidin-4-yl-4-(2-trifluoromethyl- Ii-4 RT 0.67 (I) 394.22 benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- 1.5 d]pyrimidin-5-oneC-3-5 2-Methyl-5-piperidin-4-yl-7-[1-(2-trifluoromethyl- Ii-5 RT 0.69(I)  408.29 phenyl)-ethyl]-2,4,5,7-tetrahydro-pyrazolo[3,4- 1  d]pyrimidin-6-one C-3-67-(2-Cyclopropyl-benzyl)-2-methyl-5-piperidin-4-yl- Ii-6 RT 0.67 (I) 366.28 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 1  

Synthesis of Intermediates of Formula C-4

A soln. of aldehyde BB-4 (1 eq) and amine BB-15 (1.1 eq) in MeOH (4mL/mmol) was stirred for 1.5 h at RT and cooled to 0° C. NaBH₄ (1.6 eq)was added portionwise and the rxn mixture was stirred at RT for a giventime (see Table 45). It was quenched with a 1M aq. soln. of NaOH andextracted with EtOAc. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc.

TABLE 45 t_(R) [min] MS-data Reactant Reactant time (LC/MS m/z C-4 NameBB-4 BB-15 [h] method) [M + H]⁺ C-4-1 4-[(1-Methyl-4-nitro-1H-pyrazol-BB-4-3 BB-15-2 0.5 0.61 (I) 340.39 3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester

Synthesis of Intermediates of Formula D-1

To a soln. of aldehyde BB-19 (1 eq) and amine BB-7 (1.4 eq) in THE (10mL/mmol) was added AcOH (1.5 eq) followed by NaBH(OAc)₃ (1.5 eq). Therxn mixture was stirred at RT for a given time (see Table). It wasquenched with a sat. aq. soln. of NaHCO₃ and extracted with DCM. Thecombined org. phases were dried over MgSO₄ and concentrated in vacuo.The crude was purified by CC using DCM/MeOH.

TABLE 46 t_(R) [min] MS-data Aldehyde Amine time (LC/MS m/z D-1 NameBB-19 BB-7 [h] method) [M + H]⁺ D-1-1 (4-{[1-(2-Fluoro-6-methyl- BB-19-1BB-7-1 18 0.70 (II) 377.27 phenyl)-piperidin-4-ylamino]-methyl]-2-methyl-oxazol-5-yl)- carbamic acid methyl ester

Synthesis of Intermediates of Formula E-1 Method A (NaBH(OAc)₃/THF)

To a soln. of ketone BB-26 (1 eq) and amine BB-7 (1 eq) in THE (8mL/mmol) were added AcOH (1.5 eq) and the rxn mixture was stirred for 20min at RT. NaBH(OAc)₃ (1.5 eq) was added portionwise and the rxn mixturewas stirred at RT for a given time (see Table). When necessary to reachcompletion of the rxn, an extra amount of NaBH(OAc)₃ (1 eq) was added atRT. It was partitioned between EtOAc and a sat. aq. soln. of NaHCO₃. Theorg. phase was washed with brine, dried over MgSO₄ and concentrated invacuo. The crude was purified by CC using Hept/EtOAc.

Method B (Ti(OiPr)₄/NaBH₄)

A suspension of ketone BB-26 (1 eq) and amine BB-7 (1.05 eq) in titanium(IV) isopropoxide (3 eq) was stirred at RT for 18 h. The rxn mixture wascooled to −10° C. and EtOH (1 mL/mmol), THE (1 mL/mmol) and NaBH₄ (3 eq)were sequentially added. The mixture was allowed to reach RT for 1 h andfurther stirred at RT for a given time (see Table). It was quenched withwater at 0° C. and filtered. The filtrate was extracted with EtOAc andthe combined org. phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo.

Method C (NaBH₄/TFE)

A soln. of ketone BB-26 (1 eq) and amine BB-7 (1.1 eq) in TEE (2mL/mmol) was stirred for to 2.5 h at RT and cooled to 0° C. NaBH₄ (1.5to 2 eq) was added portionwise and the rxn mixture was stirred for 20min at 0° C. and for a given time at RT (see Table). It was quenched at0° C. with a sat. aq. soln. of NaHCO₃ and extracted with DCM. Thecombined org. phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

TABLE 47 Method t_(R) [min] MS-data Reactant Reactant time (LC/MS m/zE-1 Name BB-26 BB-7 [h] method) [M + H]⁺ E-1-1[1-(2-Fluoro-6-methyl-phenyl)- BB-26-1 BB-7-1 A 0.77 (I) 362.23piperidin-4-yl]-[1-(1-methyl-4- 144    nitro-1H-pyrazol-3-yl)-ethyl]-amine E-1-2 [1-(2-Fluoro-6-methyl-phenyl)- BB-26-2 BB-7-1 B 1.01 (I)478.18 piperidin-4-yl]-{1-[4-nitro-2-(2- 2  trimethylsilanyl-ethoxymethyl)- 2H-pyrazol-3-yl]-ethyl}-amine E-1-3[1-(2-Fluoro-6-methyl-phenyl)- BB-26-4 BB-7-1 C 0.87 (I) 432.24piperidin-4-yl]-{1-[4-nitro-1- 0.5 (tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-ethyl}-amine E-1-4 (2′-Methoxy-4′-methyl-3,4,5,6- BB-26-4BB-7-2 C 0.80 (I) 445.23 tetrahydro-2H-[1,3′]bipyridinyl-4- 2.5yl)-{1-[4-nitro-1-(tetrahydro- pyran-2-yl)-1H-pyrazol-3-yl]-ethyl}-amine E-1-5 [1-(2-Chloro-6-fluoro-phenyl)- BB-26-4 BB-7-8 C 0.85(I) 452.22 piperidin-4-yl]-{1-[4-nitro-1- 0  (tetrahydro-pyran-2-yl)-1H- pyrazol-3-yl]-ethyl}-amine E-1-6[1-(2-Difluoromethyl-6-fluoro- BB-26-4 BB-7-7 C 0.86 (I) 468.25phenyl)-piperidin-4-yl]-{1-[4- 0   nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-ethyl}-amine

Synthesis of Intermediates of Formula E-2 Method A: Hydrogenation

To a soln. of intermediate E-1 (1 eq) in EtOH (7 to 7.5 mL/mmol) wasadded 10% Pd/C moistened with ˜50% water (0.02 eq) and the rxn mixturewas hydrogenated under atmospheric pressure for a given time (seeTable). It was filtered over a pad of celite and the filtrate wasconcentrated in vacuo. When necessary, the crude was purified by prep.LC-MS using method 5.

Method B: Reduction

To a soln. of intermediate E-1 (1 eq) in MeOH (9 mL/mmol) was addedCoCl₂ (1.5 eq) and the n mixture was stirred for 5 min at RT and cooledto 0° C. NaBH₄ (5 eq) was added portionwise and the mixture was stirredfor 15 min at 0° C. (see Table). It was quenched at 0° C. with water andMeOH was evaporated off. The residue was partitioned between EtOAc andwater and the aq. phase was further extracted with EtOAc. The combinedorg. phases were washed with brine, dried over MgSO₄ and concentrated invacuo.

TABLE 48 t_(R) [min] MS-data Reactant time (LC/MS m/z E-2 Name E-1 [h]method) [M + H]⁺ E-2-1[1-(4-Amino-1-methyl-1H-pyrazol-3-yl)-ethyl]-[1-(2- E-1-1 4   0.59 (I)332.28 fluoro-6-methyl-phenyl)-piperidin-4-yl]-amine E-2-2{1-[4-Amino-2-(2-trimethylsilanyl-ethoxymethyl)-2H- E-1-2 24   0.92 (I)448.25 pyrazol-3-yl]-ethyl}-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-amine E-2-3{1-[4-Amino-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-1-3 A 0.71 (I)402.09 yl]-ethyl}-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]- 2  amine E-2-4 {1-[4-Amino-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-1-4 A0.62 (I) 415.32 yl]-ethyl}-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-2   [1,3′]bipyridinyl-4-yl)-amine E-2-5{1-[4-Amino-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-1-5 B 0.68 (I)422.24 yl]-ethyl}-[1-(2-chloro-6-fluoro-phenyl)-piperidin-4-yl]-  0.25amine E-2-6 {1-[4-Amino-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-1-6 A0.70 (I) 438.30 yl]-ethyl}-[1-(2-difluoromethyl-6-fluoro-phenyl)- 2  piperidin-4-yl]-amine

Synthesis of Intermediates of Formula E-3

To a soln. of intermediate E-2 (1 eq) in MeCN (8.5 to 14.3 mL/mmol) wasadded CDI (1.2 to 1.5 eq) and the rxn mixture was stirred at a giventemperature for a given time (see Table 50). The solvent was evaporatedoff and the residue was partitioned between DCM and water or a sat. aq.soln. of NaHCO₃. The org. phase was washed with brine, dried over MgSO₄and concentrated in vacuo. When necessary the crude was purified by CCusing Hept/EtOAc.

TABLE 50 T [° C.] t_(R) [min] MS-data Reactant time (LC/MS m/z E-3 NameE-2 [h] method) [M + H]⁺ E-3-16-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]- E-2-1 RT 0.94 (I)358.44 2,7-dimethyl-2,4,6,7-tetrahydro-pyrazolo[4,3- 18  d]pyrimidin-5-one E-3-26-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- E-2-2 RT 1.17 (I)474.19 methyl-1-(2-trimethylsilanyl-ethoxymethyl)- 1.51,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5- one E-3-36-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- E-2-3 RT 1.00 (I)428.25 methyl-2-(tetrahydro-pyran-2-yl)-2,4,6,7- 0.5tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one E-3-46-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H- E-2-4 RT 0.84 (I) 441.23[1,3′]bipyridinyl-4-yl)-7-methyl-2-(tetrahydro- 0.5pyran-2-yl)-2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one E-3-56-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7- E-2-5 RT 1.02 (I)448.22 methyl-2-(tetrahydro-pyran-2-yl)-2,4,6,7- 1.5tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one E-3-66-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin- E-2-6 RT 1.02 (I)464.27 4-yl]-7-methyl-2-(tetrahydro-pyran-2-yl)-2,4,6,7- 1.5tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one

Synthesis of Intermediates of Formula E-4

To a soln. of amine BB-28 (1 eq) and aldehyde or ketone BB-12 (2 eq) inTHE (2.6 mL/mmol) were added AcOH (1.5 eq) and the rxn mixture wasstirred for 18 h at RT. NaBH₄ (1.5 eq) was added portionwise and the rxnmixture was stirred at RT for a given time (see Table). It waspartitioned between EtOAc and a sat. aq. soln. of NaHCO₃. The org. phasewas washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using Hept/EtOAc.

TABLE 49 t_(R) [min] MS-data Reactant Reactant time (LC/MS m/z E-4 NameBB-28 BB-12 [h] method) [M + H]⁺ E-4-1 1-Methyl-3-(2-trifluoromethyl-BB-28-1 BB-12-4 2 0.90 (I) 281.20 benzylamino)-1H-pyrazole-4-carbonitrile

Synthesis of Intermediates of Formula E-5 Method A (Grignard AdditionUsing Nitriles E-4)

To a stirred soln. of nitrile E-4 (1 eq) in THE (6 mL/mmol) under argonwas added dropwise at 0° C. a 3M soln. of R⁴MgBr in Et₂O (6 eq). The rxnmixture was allowed to reach RT and stirred at a given temperature for agiven time (see Table). When necessary to reach completion of the rxn,extra amounts of a 3M soln. of R⁴MgBr in Et₂O (2 eq) were added. Themixture was cooled to 0° C., quenched with a sat. aq. soln. of NH₄Cl andextracted with DCM. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc.

Method B (Heck Rxn Using Bromides E-7 or E-8)

A mixture of bromide E-7 or E-8 (1 eq), K₂CO₃ (1.2 eq), Pd(OAc)₂ (0.03eq) and 1,3-bis(diphenylphosphino)propane (0.06 eq) in a mixture of DMF(2.5 mL/mmol) and H₂O (0.6 mL/mmol) was flushed with Ar and butyl vinylether (5 eq) was added dropwise at RT. The rxn mixture was heated at agiven temperature for a given time (see Table). After cooling to RT, a1M aq. solution of HCl (2 mL/mmol) was added and the mixture was stirredfor 1 h at RT. It was neutralised with a sat. aq. soln. of NaHCO₃ andextracted with EtOAc. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc.

TABLE 50 Reactant Reactant MethodT t_(R) [min] MS-data E-4, E-7 R⁴MgBror [° C.] (LC/MS m/z E-5 Name or E-8 vinyl ether time [h] method) [M +H]⁺ E-5-1 1-[1-Methyl-3-(2- E-4-1 MeMgBr, as A 0.91 (I) 298.22trifluoromethyl- a 3M soln. in  80 benzylamino)-1H- Et₂O  3pyrazol-4-yl]-ethanone E-5-2 1-[1-(Tetrahydro-pyran-2- E-8-1 Butyl vinylB 1.01 (I) 368.24 yl)-3-(2-trifluoromethyl- ether 105 benzylamino)-1H- 18 pyrazol-4-yl]-ethanone E-5-3 1-[3-(2-Cyclopropyl- E-7-2 Butyl vinylB 0.89 (I) 270.35 benzylamino)-1-methyl- ether 100 1H-pyrazol-4-yl]-  3ethanone E-5-4 1-[3-(2-Cyclopropyl- E-8-2 Butyl vinyl B 1.00 (I) 340.24benzylamino)-1- ether 100 (tetrahydro-pyran-2-yl)-  2 1H-pyrazol-4-yl]-ethanone E-5-5 1-{1-Methyl-3-[(3- E-7-4 Butyl vinyl B 0.76 (I) 299.22trifluoromethyl-pyridin-2- ether 100 ylmethyl)-amino]-1H-  18pyrazol-4-yl}-ethanone

Synthesis of Intermediates of Formula E-6 Method A

A suspension of ketone E-5 or E-10 (1 eq) and amine BB-7 (1.1 to 1.2 eq)in titanium (IV) isopropoxide (3 to 5 eq) was stirred at RT for 18 h.The rxn mixture was cooled to 0° C. and EtOH (i to 2.5 mL/mmol), THE (1mL/mmol) and NaBH₄ (3 eq) were sequentially added. The mixture wasstirred at RT for a given time (see Table), quenched with water at 0° C.and when necessary filtered over a pad of celite. It was extracted withEtOAc and the combined org. phases were washed with brine, dried overMgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc.

Method B

To a mixture of ketone E-5 or E-10 (1 eq) and amine [ ]-7 (1.1 to 1.2eq) in THE (3 mL/mmol) was added titanium (IV) isopropoxide (3 to 4.4eq) and the soln. was stirred at RT for 18 h. It was cooled to 0° C. andMeOH (6 mL/mmol) and NaBH₄ (1.3 to 2 eq) were sequentially added. Afterstirring for a given time at RT (see Table), it was quenched with waterand a 1M soln. of NaOH and extracted with EtOAc. When necessary afiltration over a pad of celite was performed. The combined org. phaseswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using Hept/EtOAc or by prep. LC-MS using method5 or 8.

TABLE 51 Reactant t_(R) [min] MS-data E-5 or Reactant Method (LC/MS m/zE-6 Name E-10 BB-7 time [h] method) [M + H]⁺ E-6-1[1-(2-Fluoro-6-methyl- E-5-1 BB-7-1 1   0.89 (I) 490.28phenyl)-piperidin-4-yl]-{1-[1- methyl-3-(2-trifluoromethyl-benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-2 [1-(2-Fluoro-6-methyl-E-5-2 BB-7-1 A 0.96 (I) 560.38 phenyl)-piperidin-4-yl]-{1-[1- 18  (tetrahydro-pyran-2-yl)-3-(2- trifluoromethyl-benzylamino)-1H-pyrazol-4-yl]-ethyl}-amine E-6-3 {1-[1-Cyclopropyl-3-(2- E-10-1BB-7-1 A 0.98 (I) 516.39 trifluoromethyl-benzylamino)- 1  1H-pyrazol-4-yl]-ethyl}-[1-(2- fluoro-6-methyl-phenyl)-piperidin-4-yl]-amine E-6-4 {1-[1-Cyclopropyl-3-(2- E-10-1 BB-7-7 A 0.93(I) 552.33 trifluoromethyl-benzylamino)- 0.51H-pyrazol-4-yl]-ethyl}-[1-(2- difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-amine E-6-5 [1-(2-Difluoromethyl-6-fluoro- E-5-1BB-7-7 A 0.92 (I) 526.38 phenyl)-piperidin-4-yl]-{1-[1- 0.5methyl-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amineE-6-6 {1-[3-(2-Cyclopropyl- E-5-3 BB-7-1 B 0.91 (I) 462.36benzylamino)-1-methyl-1H- 1   pyrazol-4-yl]-ethyl}-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-amine E-6-7[1-(2-Chloro-6-fluoro- E-5-1 BB-7-8 A 0.89 (I) 510.26phenyl)-piperidin-4-yl]-{1-[1- 0.5 methyl-3-(2-trifluoromethyl-benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-8 [1-(2-Chloro-6-fluoro-E-5-3 BB-7-8 B 0.91 (I) 482.08 phenyl)-piperidin-4-yl]-{1-[3- 18  (2-cyclopropyl-benzylamino)- 1-methyl-1H-pyrazol-4-yl]- ethyl}-amineE-6-9 {1-[3-(2-Cyclopropyl- E-5-3 BB-7-7 B 0.92 (I) 498.15benzylamino)-1-methyl-1H- 0.5 pyrazol-4-yl]-ethyl}-[1-(2-difluoromethyl-6-fluoro- phenyl)-piperidin-4-yl]-amine E-6-10{1-[3-(2-Cyclopropyl- E-5-3 BB-7-9 B 0.92 (I) 488.37benzylamino)-1-methyl-1H- 0.5 pyrazol-4-yl]-ethyl}-[1-(2-cyclopropyl-6-fluoro-phenyl)- piperidin-4-yl]-amine E-6-11(2′-Methoxy-4′-methyl- E-5-1 BB-7-2 B 0.86 (I) 503.333,4,5,6-tetrahydro-2H- 2   [1,3′]bipyridinyl-4-yl)-{1-[1-methyl-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amineE-6-12 [1-(2-Cyclopropyl-6-fluoro- E-5-1 BB-7-9 B 0.93 (I) 516.24phenyl)-piperidin-4-yl]-{1-[1- 0.5 methyl-3-(2-trifluoromethyl-benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-13[1-(2-Chloro-6-fluoro- E-10-1 BB-7-8 A 0.93 (I) 536.22phenyl)-piperidin-4-yl]-{1-[1- 0.5 cyclopropyl-3-(2-trifluoromethyl-benzylamino)- 1H-pyrazol-4-yl]-ethyl}-amine E-6-14{1-[1-Cyclopropyl-3-(2- E-10-2 BB-7-1 B 0.95 (I) 488.34cyclopropyl-benzylamino)- 3   1H-pyrazol-4-yl]-ethyl}-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-amine E-6-15[1-(2-Chloro-6-fluoro- E-10-2 BB-7-8 B 0.94 (I) 508.32phenyl)-piperidin-4-yl]-{1-[1- 3   cyclopropyl-3-(2-cyclopropyl-benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-16{1-[1-Cyclopropyl-3-(2- E-10-1 BB-7-2 A 0.91 (I) 529.18trifluoromethyl-benzylamino)- 0.5 1H-pyrazol-4-yl]-ethyl}-(2′-methoxy-4′-methyl-3,4,5,6- tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amineE-6-17 (4′-Difluoromethyl-2′- E-5-1 BB-7-10 A 0.88 (I) 539.26methoxy-3,4,5,6-tetrahydro- 1   2H-[1,3′]bipyridinyl-4-yl)-{1-[1-methyl-3-(2- trifluoromethyl-benzylamino)-1H-pyrazol-4-yl]-ethyl}-amine E-6-18 [1-(2-Difluoromethyl-6-fluoro-E-5-2 BB-7-7 A 0.97 (I) 596.33 phenyl)-piperidin-4-yl]-{1-[1- 0.5(tetrahydro-pyran-2-yl)-3-(2- trifluoromethyl-benzylamino)-1H-pyrazol-4-yl]-ethyl}-amine E-6-19 [1-(2-Chloro-6-fluoro- E-5-2 BB-7-8A 0.98 (I) 580.31 phenyl)-piperidin-4-yl]-{1-[1- 1  (tetrahydro-pyran-2-yl)-3-(2- trifluoromethyl-benzylamino)-1H-pyrazol-4-yl]-ethyl}-amine E-6-20 (4′-Difluoromethyl-2′- E-5-2BB-7-10 A 0.98 (I) 609.09 methoxy-3,4,5,6-tetrahydro- 0.52H-[1,3′]bipyridinyl-4-yl)-{1- [1-(tetrahydro-pyran-2-yl)-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-21[1-(2-Fluoro-6-methyl- E-5-5 BB-7-1 B 0.83 (I) 491.26phenyl)-piperidin-4-yl]-(1-{1- 0.5 methyl-3-[(3-trifluoromethyl-pyridin-2-ylmethyl)-amino]- 1H-pyrazol-4-yl}-ethyl)- amine E-6-22(2′-Methoxy-4′-methyl- E-5-5 BB-7-2 B 0.77 (I) 504.263,4,5,6-tetrahydro-2H- 0.5 [1,3′]bipyridinyl-4-yl)-(1-{1-methyl-3-[(3-trifluoromethyl- pyridin-2-ylmethyl)-amino]-1H-pyrazol-4-yl}-ethyl)- amine E-6-23 {1-[1-Cyclopropyl-3-(2- E-10-1BB-7-10 B 0.92 (I) 565.27 trifluoromethyl-benzylamino)- 1  1H-pyrazol-4-yl]-ethyl}-(4′- difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine E-6-24[1-(2-Bromo-6-fluoro- E-10-1 BB-7-11 B 0.93 (I) 580.20phenyl)-piperidin-4-yl]-{1-[1- 1.5 cyclopropyl-3-(2-trifluoromethyl-benzylamino)- 1H-pyrazol-4-yl]-ethyl}-amine E-6-25(2′-Methoxy-4′- E-5-1 BB-7-12 A 0.93 (I) 557.32 trifluoromethyl-3,4,5,6-1.5 tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-{1-[1-methyl-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amineE-6-26 {1-[3-(2-Cyclopropyl- E-5-3 BB-7-2 B 0.86 (I) 475.31benzylamino)-1-methyl-1H- 1.5 pyrazol-4-yl]-ethyl}-(2′-methoxy-4′-methyl-3,4,5,6- tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amineE-6-27 {1-[3-(2-Cyclopropyl- E-5-3 BB-7-10 B 0.91 (I) 511.31benzylamino)-1-methyl-1H- 1.5 pyrazol-4-yl]-ethyl}-(4′-difluoromethyl-2′-methoxy- 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-amine E-6-28 {1-[3-(2-Cyclopropyl- E-5-4 BB-7-10B 0.98 (I) 581.38 benzylamino)-1-(tetrahydro- 1  pyran-2-yl)-1H-pyrazol-4-yl]- ethyl}-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro- 2H-[1,3′]bipyridinyl-4-yl)- amine E-6-29[1-(2-Chloro-6-fluoro- E-5-4 BB-7-8 B 0.98 (I) 552.36phenyl)-piperidin-4-yl]-{1-[3- 1   (2-cyclopropyl-benzylamino)-1-(tetrahydro-pyran-2-yl)-1H- pyrazol-4-yl]-ethyl}-amine E-6-30{1-[3-(2-Cyclopropyl- E-5-3 BB-7-12 A 0.91 (I) 529.14benzylamino)-1-methyl-1H- 1   pyrazol-4-yl]-ethyl}-(2′-methoxy-4′-trifluoromethyl- 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-amine E-6-31 (4′-Chloro-2′-methoxy- E-5-1BB-7-13 A 0.87 (I) 523.21 3,4,5,6-tetrahydro-2H- 0.5[1,3′]bipyridinyl-4-yl)-{1-[1- methyl-3-(2-trifluoromethyl-benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-32(4′-Chloro-2′-methoxy- E-5-3 BB-7-13 A 0.87 (I) 495.263,4,5,6-tetrahydro-2H- 0.5 [1,3′]bipyridinyl-4-yl)-{1-[3-(2-cyclopropyl-benzylamino)-1- methyl-1H-pyrazol-4-yl]- ethyl}-amine E-6-33{1-[1-Cyclopropyl-3-(2- E-10-2 BB-7-2 B 0.90 (I) 501.37cyclopropyl-benzylamino)- 0.5 1H-pyrazol-4-yl]-ethyl}-(2′-methoxy-4′-methyl-3,4,5,6- tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amineE-6-34 {1-[1-Cyclopropyl-3-(2- E-10-2 BB-7-10 B 0.95 (I) 537.38cyclopropyl-benzylamino)- 0.5 1H-pyrazol-4-yl]-ethyl}-(4′-difluoromethyl-2′-methoxy- 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-amine E-6-35 [1-(2-Bromo-6-fluoro- E-5-3 BB-7-11B 0.93 (I) 526.28 phenyl)-piperidin-4-yl]-{1-[3- 1  (2-cyclopropyl-benzylamino)- 1-methyl-1H-pyrazol-4-yl]- ethyl}-amine

Synthesis of Intermediates of Formula E-7 Method A

A soln. of amine BB-34 (1 eq) and aldehyde or ketone BB-12 (1.05 to 1.1eq) in MCOH (2 to 4 mL/mmol) was stirred for 1 h at RT. NaBH₄ (1.6 to 2eq) was added portionwise at 0° C. and the rxn mixture was stirred at agiven temperature for a given time (see Table 52). It was quenched withH₂O at 0° C. and extracted with EtOAc. The combined org. phases werewashed with brine, dried over MgSO₄ and concentrated in vacuo. Whennecessary, the crude was purified by CC using EtOAc/MeOH.

Method B

A soln. of amine BB-34 (1 eq), aldehyde or ketone BB-12 (1.1 eq) andAcOH (1.1 eq) in MeOH (1.5 mL/mmol) was stirred under Ar for 1 h at RT.Molybdenum(VI) dichloride dioxide (0.05 eq) in MeOH (1.5 mL/mmol) wasadded at RT followed by phenylsilane (1.5 eq). The rxn mixture wasstirred at a given temperature for a given time (see Table 52) andquenched with a sat. soln. of NaHCO₃. It was extracted with DCM and thecombined org. phases were dried over MgSO₄ and concentrated in vacuo.The crude was purified by CC using EtOAc/MeOH.

TABLE 52 Method t_(R) [min] MS-data Reactant Reactant T [° C.] (LC/MSm/z E-7 Name BB-34 BB-12 time [h] method) [M + H]⁺ E-7-1(4-Bromo-1H-pyrazol-3-yl)- BB-34-1 BB-12-4 A 0.91 (I) 320.02(2-trifluoromethyl-benzyl)- 0   amine 1.5 E-7-2 (4-Bromo-1-methyl-1H-BB-34-2 BB-12-5 A 0.97 (I) 305.85 pyrazol-3-yl)-(2-cydopropyl- RTbenzyl)-amine 2.5 E-7-3 (4-Bromo-1H-pyrazol-3-yl)- BB-34-1 BB-12-5 A0.89 (I) 292.18 (2-cyclopropyl-benzyl)-amine RT 1   E-7-4(4-Bromo-1-methyl-1H- BB-34-2 BB-12-1 B 0.87 (I) 335.08pyrazol-3-yl)-(3- RT trifluoromethyl-pyridin-2- 18   ylmethyl)-amine

Synthesis of Intermediates of Formula E-8

To a suspension or solution of the intermediate E-7 (1 eq) in DCM (2 to4 mL/mmol) was added TsOH (0.1 eq) and 3,4-dihydro-2H-pyran (1.3 eq).The rxn mixture was stirred at a given temperature for a given time (seeTable 53) and quenched with a sat. aq. soln. of NaHCO₃. It was extractedwith DCM, the org. phase was washed with a sat. aq. soln. of NaHCO₃ andbrine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc.

TABLE 53 T [° C.] t_(R) [min] MS-data Reactant time (LC/MS m/z E-8 NameE-7 [h] method) [M + H]⁺ E-8-1[4-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-7-1 50 1.08 (I)404.09 yl]-(2-trifluoromethyl-benzyl)-amine 20 E-8-2[4-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-7-3 45 1.06 (I)376.17 yl]-(2-cydopropyl-benzyl)-amine 18

Synthesis of Intermediates of Formula E-9

To a soln. of THP-protected intermediate E-5 (1 eq) in DCM (2 mL/mmol)was added dropwise TFA (1.5 mL/mmol). The soln. was stirred at RT for agiven time (see Table 54), quenched at 0° C. with a 1 M aq. soln. ofNaOH until pH 10-11 and extracted with DCM. The combined org. phaseswere dried over MgSO₄ and concentrated in vacuo. The crude was purifiedby CC using Hept/EtOAc.

TABLE 54 T [° C.] t_(R) [min] MS-data Reactant time (LC/MS m/z E-9 NameE-5 [h] method) [M + H]⁺ E-9-1 1-[3-(2-Trifluoromethyl-benzylamino)-E-5-2 RT 0.82 (I) 284.16 1H-pyrazol-4-yl]-ethanone  1 E-9-21-[3-(2-Cyclopropyl-benzylamino)-1H- E-5-4 RT 0.82 (I) 256.33pyrazol-4-yl]-ethanone 72

Synthesis of Intermediates of Formula E-10

A mixture of intermediates E-9 (1 eq), boron species BB-10 (2 eq),Na₂CO₃(2 eq), 2,2′-bipyridyl (1 eq) and Cu(OAc)₂ (1 eq) in toluene (10to 12 mL/mmol) was flushed with N₂ and heated at a given temperature fora given time (see Table 55). It was partitioned between EtOAc or DCM anda sat. aq. soln. of NaHCO₃ and the org. phase was washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc.

TABLE 55 t_(R) [min] MS-data Reactant Reactant T [° C.] (LC/MS- m/z E-10Name E-9 BB-10 time [h] method) [M + H]⁺ E-10-1 1-[1-Cyclopropyl-3-(2-E-9-1 Cyclopropyl 70   0.97 (I) 324.22 trifluoromethyl-benzylamino)-1H-boronic acid 2.5 pyrazol-4-yl]-ethanone E-10-21-[1-Cyclopropyl-3-(2-cyclopropyl- E-9-2 Cyclopropyl 80   0.95 (I)296.33 benzylamino)-1H-pyrazol-4-yl]- boronic acid 2   ethanone

Synthesis of compounds of formula Ia Method A1 (Alkylation of A-3 orE-3: NaH/THF)

To a soln. of intermediate A-3 or E-3 (1 eq) in a mixture of anh. THE (3to 7.3 mL/mmol) and anh. DMF (0 to 0.7 mL/mmol) was added NaH (1.5 to 10eq, as a 60% dispersion in mineral oil) at 0° C. The suspension wasstirred for 10 min and halide BB-9 (1.1 to 1.5 eq) was added at 0° C.The rxn mixture was stirred at a given temperature for a given timeunder possible microwave irradiation (see Table). When necessary toreach completion of the rxn an extra amount of NaH (0.5 eq, as a 60%dispersion in mineral oil) and/or halide BB-9 (0.5 eq) was added. Themixture was quenched with water or a sat. aq. soln. of NaHCO₃ andextracted with EtOAc. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc or by prep. LC-MS using method 1, 2 or 5.

Method A2 (Alkylation of A-3 or E-3 Using NaH/THF Followed bySaponification)

Similar to method A1 except that the rxn mixture was quenched with a 2Maq. soln. of NaOH and stirred ON at RT before the extraction with EtOAc.

Method B (Mitsunobu with A-3 or E-3)

To a soln. or suspension of intermediate A-3 or E-3 (1 eq) and alcoholBB-9 (1.1 to 6 eq) in toluene (3.4 to 24 mL/mmol) was added a 1M soln.of (tributylphosphoranylidene)acetonitrile in toluene (1.1 to 2 eq)under argon. The rxn mixture was heated to a given temperature andstirred for a given time (see Table). When necessary to reach completionof the rxn, extra amounts of a 1M soln. of(tributylphosphoranylidene)acetonitrile in toluene (0.2 eq) weresequentially added under argon. It was quenched with water or a sat. aq.soln. of NaHCO₃ and extracted with EtOAc or DCM. The combined org.phases were washed with brine, dried over MgSO₄ and concentrated invacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH. Whennecessary, an additional purification by prep. LC-MS using methods 2, 3,4 or 5 was performed.

Method C (Cyclisation from B-3)

To a suspension of intermediate B-3 (1 eq) in MeCN (5.1 to 11.2 mL/mmol)was added CDI (5 to 7 eq) and the rxn mixture was stirred at a giventemperature for a given time (see Table). The solvent was evaporated offand the residue was partitioned between EtOAc and water. The org. phasewas washed with brine, dried over MgSO₄ and concentrated in vacuo. Whennecessary, the crude was purified by CC using Hept/EtOAc/MeOH.

Method D (Alkylations of A-3: K₂CO₃/DMF)

To a stirred soln. of intermediate A-3 (1 eq) in DMF (3.9 to 4.7mL/mmol) was added K₂C₃ (1.5 to 3 eq) followed by the appropriate halideBB-9 (1.3 to 1.5 eq). The rxn mixture was stirred at a given temperaturefor a given time (see Table). When necessary to reach completion of therxn, extra amounts of halide BB-9 (1 eq) were added at RT. It waspartitioned between EtOAc and H₂O. The org. phase was washed with waterand brine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc and/or DCM/MeOH.

Method E (Cyclisation from E-6)

To a suspension of diamine E-6 (1 eq) in MeCN (or DCM, respectively) (8to 12.7 mL/mmol) was added DSC (or CDT, respectively) (1.2 to 1.3 eq)and optionally Et₃N (3 eq) at RT. The rxn mixture was stirred at a giventemperature for a given time (see Table) and partitioned between EtOAcor DCM and a 1 M soln. of NaOH or a sat. soln. of NaHCO₃. The org. phasewas washed with water and brine, dried over MgSO₄ and concentrated invacuo. The crude was purified by CC using Hept/EtOAc or by prep. LC-MSusing method 4, 5, 8 or 10.

TABLE 56 Reactant Method t_(R) [min] MS-data A-3, B-3, Reactant T [° C.](LC/MS- m/z Ia Name E-3 or E-6 BB-9 time [h] method) [M + H]⁺ Ia-1A6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-1A BB-9-1 A1 1.30 (I)618.26 yl]-4-(2-trifluoromethyl-benzyl)-1-(2- RTtrimethylsilanyl-ethoxymethyl)-1,4,6,7- 66  tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 1) Ia-1B6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-1B BB-9-1 A1 1.29 (I)618.28 yl]-4-(2-trifluoromethyl-benzyl)-2-(2- RTtrimethylsilanyl-ethoxymethyl)-2,4,6,7- 2  tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 195) Ia-25-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-2 BB-9-1 A1 1.31 (I)618.38 yl]-7-(2-trifluoromethyl-benzyl)-2-(2- RTtrimethylsilanyl-ethoxymethyl)-2,4,5,7- 24  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 5) Ia-36-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-3 BB-9-2 A1  1.00 (II)504.17 yl]-2-methyl-4-(3-trifluoromethyl-pyrazin-2- RTylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- 18   d]pyrimidin-5-one(Example 11) Ia-4 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-3BB-9-3 B  1.04 (II) 503.19 yl]-2-methyl-4-(4-trifluoromethyl-pyridin-3-110    ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- 3   d]pyrimidin-5-one(Example 12) Ia-5 1-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-4BB-9-1 A1  1.12 (II) 618.17 yl]-3-(2-trifluoromethyl-benzyl)-7-(2- RTtrimethylsilanyl-ethoxymethyl)-1,3,6,7- 18   tetrahydro-purin-2-one(Example 13) Ia-6 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-3BB-9-4 B  1.01 (II) 503.16 yl]-2-methyl-4-(3-trifluoromethyl-pyridin-2-110    ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- 18   d]pyrimidin-5-one(Example 15) Ia-7 7-(2-Cyclopropoxy-benzyl)-5-[1-(2-fluoro-6- A-3-5BB-9-5 A1  1.06 (II) 490.15 methyl-phenyl)-piperidin-4-yl]-2-methyl- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 18   6-one (Example 21)Ia-8 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- B-3-1 — C  1.00 (II)503.09 yl]-2-methyl-7-(3-trifluoromethyl-pyridin-2- 80  ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 2   d]pyrimidin-6-one(Example 22) Ia-9 7-(6-Chloro-3-trifluoromethyl-pyridin-2- B-3-2 — C 1.05 (II) 537.07 ylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)- 80  piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro- 2  pyrazolo[3,4-d]pyrimidin-6-one (Example 35) Ia-105-[(R)-1-(2-Fluoro-6-methyl-phenyl)- A-3-6 BB-9-1 A1  0.91 (II) 488.09pyrrolidin-3-yl]-2-methyl-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one (Example 55) Ia-115-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- B-3-3 — C  1.06 (II) 520.07yl]-7-(2-fluoro-6-trifluoromethyl-benzyl)-2- 80  methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 72   d]pyrimidin-6-one (Example61) Ia-12 3-Benzyl-6-[1-(2-fluoro-6-methyl-phenyl)- A-3-7 BB-9-1 D  1.10(II) 579.16 piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)- 45 and 803,4,6,7-tetrahydro-[1,2,3]triazolo[4,5- 18 and 5 d]pyrimidin-5-one Ia-136-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-8 BB-9-6 B  1.12 (II)503.15 yl]-2-methyl-4-(2-trifluoromethyl-benzyl)- 110   6,7-dihydro-4H-oxazolo[5,4-d]pyrimidin-5-  0.25 one (Example 89) Ia-146-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-9 BB-9-6 B  1.12 (II)519.04 yl]-2-methyl-4-(2-trifluoromethyl-benzyl)- 110   6,7-dihydro-4H-thiazolo[5,4-d]pyrimidin-5- 0.5 one (Example 90) Ia-156-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-10 BB-9-4 B 1.17 (I)504.17 yl]-2-methyl-4-(3-trifluoromethyl-pyridin-2- 110   ylmethyl)-2,4,6,7-tetrahydro- 2   [1,2,3]triazolo[4,5-d]pyrimidin-5-one(Example 128) Ia-16 5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-3-11BB-9-7 A1 1.01 (I) 516.14 2H-[1,3′]bipyridinyl-4-yl)-2-methyl-7-(3-microwave trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7- 100   tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one  0.75 (Example 138) Ia-176-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-3-12 BB-9-6 B 1.17 (I)516.02 2H-[1,3′]bipyridinyl-4-yl)-2-methyl-4-(2- 110   trifluoromethyl-benzyl)-2,4,6,7-tetrahydro- 1  [1,2,3]triazolo[4,5-d]pyrimidin-5-one (Example 145) Ia-186-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-3-12 BB-9-4 B 1.07 (I)517.11 2H-[1,3′]bipyridinyl-4-yl)-2-methyl-4-(3- 110   trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7- 18  tetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5- one (Example 146) Ia-195-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-2 BB-9-7 D 1.26 (I)619.39 yl]-7-(3-trifluoromethyl-pyridin-2-ylmethyl)- 140   2-(2-trimethylsilanyl-ethoxymethyl)-2,4,5,7- 4  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one microwave Ia-205-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-3-13 BB-9-1 A1 1.27 (I)631.22 2H-[1,3′]bipyridinyl-4-yl)-7-(2- RTtrifluoromethyl-benzyl)-2-(2-trimethylsilanyl- 18  ethoxymethyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one(Example 196) Ia-21 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-1BBB-9-7 A1 1.24 (I) 619.25 yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)-RT 2-(2-trimethylsilanyl-ethoxymethyl)-2,4,6,7- 18  tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 199) Ia-226-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-3-1 BB-9-1 A1 1.22 (I)516.07 yl]-2,7-dimethyl-4-(2-trifluoromethyl- RTbenzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- 3   d]pyrimidin-5-one Ia-237-(2-Bromo-6-trifluoromethyl-benzyl)-5-[1- A-3-2 BB-9-8 A1 1.35 (I)696.27 (2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2- RT(2-trimethylsilanyl-ethoxymethyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-246-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-3-14 BB-9-1 A1 1.25 (I)631.40 2H-[1,3′]bipyridinyl-4-yl)-4-(2- RTtrifluoromethyl-benzyl)-1-(2-trimethylsilanyl- 18  ethoxymethyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one(Example 216) Ia-25 5-[1-(2-Fluoro-6-methyl-phenyl)-4-methyl- A-3-15BB-9-1 A1 1.20 (I) 516.26 piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-RT benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 24   d]pyrimidin-6-one(Example 217) Ia-26 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-6-1 —E 1.21 (I) 516.22 yl]-2,4-dimethyl-7-(2-trifluoromethyl- 40  benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 3.5 d]pyrimidin-6-one Ia-275-[1-(2-Fluoro-6-methyl-phenyl)-azepan-4- A-3-16 BB-9-1 A1 1.22 (I)516.17 yl]-2-methyl-7-(2-trifluoromethyl-benzyl)- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 5   6-one Ia-287-(2-Cyclopropyl-benzyl)-5-[1-(2-fluoro-6- A-3-5 BB-9-9 B 1.19 (I)474.23 methyl-phenyl)-piperidin-4-yl]-2-methyl- 110   2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 1   6-one (Example 228)Ia-29 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-1A BB-9-7 A1 1.24(I) 619.22 yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)- RT1-(2-trimethylsilanyl-ethoxymethyl)-1,4,6,7- 48  tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 230) Ia-305-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-10 A1 1.22 (I)476.21 yl]-7-(2-isopropyl-benzyl)-2-methyl-2,4,5,7- RTtetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 18   (Example 231) Ia-315-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-11 A1 1.20 (I)518.19 yl]-2-methyl-7-(2-trifluoromethoxy-benzyl)- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 18   6-one (Example 232)Ia-32 7-(2-Chloro-benzyl)-5-[1-(2-fluoro-6-methyl- A-3-5 BB-9-12 A1 1.17(I) 468.13 phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7- RTtetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 18   (Example 233) Ia-335-[1-(2-Fluoro-6-methyl-phenyl)-3-methyl- A-3-17 BB-9-1 A1 1.15 (I)502.16 pyrrolidin-3-yl]-2-methyl-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one Ia-347-(2,4-Difluoro-6-isopropoxy-benzyl)-5-[1- A-3-5 BB-9-13 B 1.18 (I)528.23 (2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2- 110   methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 2   d]pyrimidin-6-one (Example236) Ia-35 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-3-2 BB-9-1 A11.31 (I) 632.19 yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-1- RT(2-trimethylsilanyl-ethoxymethyl)-1,4,6,7- 18  tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 237) Ia-365-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-14 B 1.16 (I)523.16 yl]-2-methyl-7-(2-methyl-4-trifluoromethyl- 110   thiazol-5-ylmethyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one (Example 240) Ia-375-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-3- A-3-18 BB-9-1 A1 1.17 (I)502.18 yl]-2-methyl-7-(2-trifluoromethyl-benzyl)- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 18   6-one Ia-385-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-15 B 1.21 (I)516.21 yl]-2-methyl-7-[1-(2-trifluoromethyl-phenyl)- 110   ethyl]-2,4,5,7-tetrahydropyrazolo[3,4- 1   d]pyrimidin-6-one Ia-395-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-16 A2 1.15 (I)449.95 yl]-7-(2-hydroxy-benzyl)-2-methyl-2,4,5,7- RTtetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 5   Ia-405-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-17 B 1.19 (I)478.22 yl]-7-(4-isopropyl-pyrimidin-5-ylmethyl)-2- 110   methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 5.5 d]pyrimidin-6-one (Example249) Ia-41 7-(2-Ethoxy-benzyl)-5-[1-(2-fluoro-6- A-3-5 BB-9-18 B 1.16(I) 478.19 methyl-phenyl)-piperidin-4-yl]-2-methyl- 110   2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 1   6-one (Example 252)Ia-42 4-(2-Cyclopropyl-benzyl)-6-[1-(2-fluoro-6- A-3-3 BB-9-9 B 1.20 (I)474.20 methyl-phenyl)-piperidin-4-yl]-2-methyl- 110   2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 1   5-one (Example 259)Ia-43 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-3 BB-9-10 A1 1.22(I) 476.20 yl]-4-(2-isopropyl-benzyl)-2-methyl-2,4,6,7- RTtetrahydro-pyrazolo[4,3-d]pyrimidin-5-one 18   (Example 260) Ia-446-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-3 BB-9-15 B 1.18 (I)516.21 yl]-2-methyl-4-[1-(2-trifluoromethyl-phenyl)- 110   ethyl]-2,4,6,7-tetrahydro-pyrazolo[4,3- 2   d]pyrimidin-5-one Ia-455-[1-(2-Fluoro-6-methyl-phenyl)-azetidin-3- A-3-19 BB-9-6 B  1.17 (IV)474.01 yl]-2-methyl-7-(2-trifluoromethyl-benzyl)- 100   2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 1   6-one (Example 264)Ia-46 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-19 B 0.89(I) 494.21 yl]-7-(4-isopropoxy-pyridazin-3-ylmethyl)-2- 100   methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 18   d]pyrimidin-6-one (Example267) Ia-47 4-(2-Cyclopropyl-benzyl)-6-[1-(2-fluoro-6- E-3-3 BB-9-9 B1.22 (I) 558.34 methyl-phenyl)-piperidin-4-yl]-7-methyl-2- 110   (tetrahydro-pyran-2-yl)-2,4,6,7-tetrahydro- 3.5pyrazolo[4,3-d]pyrimidin-5-one (mixture of diastereoisomers) (Example268) Ia-48 4-(2-Cyclopropyl-benzyl)-6-(2′-methoxy-4′- E-3-4 BB-9-9 B1.14 (I) 571.34 methyl-3,4,5,6-tetrahydro-2H- 110   [1,3′]bipyridinyl-4-yl)-7-methyl-2- 18  (tetrahydro-pyran-2-yl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (mixture of diastereoisomers) (Example269) Ia-51 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-6-2 — E 1.25(I) 586.40 yl]-4-methyl-2-(tetrahydro-pyran-2-yl)-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5pyrazolo[3,4-d]pyrimidin-6-one (mixture of +50 diastereoisomers)(Example 313)  0.25 Ia-53 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-E-3-4 BB-9-6 B 1.14 (I) 599.35 2H-[1,3′]bipyridinyl-4-yl)-7-methyl-2-110    (tetrahydro-pyran-2-yl)-4-(2-trifluoromethyl- 18  benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (mixture ofdiastereoisomers) Ia-54 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-E-3-3 BB-9-1 A1 1.21 (I) 586.35yl]-7-methyl-2-(tetrahydro-pyran-2-yl)-4-(2- RTtrifluoromethyl-benzyl)-2,4,6,7-tetrahydro- 18  pyrazolo[4,3-d]pyrimidin-5-one (mixture of diastereoisomers) (Example294) Ia-55 2-Cyclopropyl-5-[1-(2-fluoro-6-methyl- E-6-3 — E 1.24 (I)542.28 phenyl)-piperidin-4-yl]-4-methyl-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 72  pyrazolo[3,4-d]pyrimidin-6-one Ia-562-Cyclopropyl-5-[1-(2-difluoromethyl-6- E-6-4 — E 1.24 (I) 578.15fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 5  pyrazolo[3,4-d]pyrimidin-6-one Ia-575-[1-(2-Difluoromethyl-6-fluoro-phenyl)- E-6-5 — E 1.22 (I) 552.30piperidin-4-yl]-2,4-dimethyl-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one Ia-587-(2-Cyclopropyl-benzyl)-5-[1-(2-fluoro-6- E-6-6 — E 1.22 (I) 488.34methyl-phenyl)-piperidin-4-yl]-2,4-dimethyl- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 20   6-one Ia-595-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-7 — E 1.23 (I) 536.23yl]-2,4-dimethyl-7-(2-trifluoromethyl- RTbenzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 20   d]pyrimidin-6-one Ia-605-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-8 — E 1.20 (I) 508.32yl]-7-(2-cyclopropyl-benzyl)-2,4-dimethyl- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 5   6-one Ia-617-(2-Cyclopropyl-benzyl)-5-[1-(2- E-6-9 — E 1.18 (I) 524.31difluoromethyl-6-fluoro-phenyl)-piperidin-4- RTyl]-2,4-dimethyl-2,4,5,7-tetrahydro- 4   pyrazolo[3,4-d]pyrimidin-6-oneIa-62 7-(2-Cyclopropyl-benzyl)-5-[1-(2- E-6-10 — E 1.22 (I) 514.05cyclopropyl-6-fluoro-phenyl)-piperidin-4-yl]- RT2,4-dimethyl-2,4,5,7-tetrahydro- 3   pyrazolo[3,4-d]pyrimidin-6-oneIa-63 6-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-3-5 BB-9-1 A1 1.25(I) 606.32 yl]-7-methyl-2-(tetrahydro-pyran-2-yl)-4-(2- RTtrifluoromethyl-benzyl)-2,4,6,7-tetrahydro- 18  pyrazolo[4,3-d]pyrimidin-5-one (mixture of diastereoisomers) Ia-646-[1-(2-Difluoromethyl-6-fluoro-phenyl)- E-3-6 BB-9-1 A1 1.24 (I) 622.34piperidin-4-yl]-7-methyl-2-(tetrahydro- RTpyran-2-yl)-4-(2-trifluoromethyl-benzyl)- 18  2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (mixture ofdiastereoisomers) Ia-65 5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-E-6-11 — E 1.13 (I) 529.13 2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2-RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one Ia-665-[1-(2-Cyclopropyl-6-fluoro-phenyl)- E-6-12 — E 1.22 (I) 542.33piperidin-4-yl]-2,4-dimethyl-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 2  pyrazolo[3,4-d]pyrimidin-6-one Ia-675-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-13 — E 1.26 (I) 562.05yl]-2-cyclopropyl-4-methyl-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one Ia-682-Cyclopropyl-7-(2-cyclopropyl-benzyl)-5- E-6-14 — E 1.23 (I) 514.16[1-(2-fluoro-6-methyl-phenyl)-piperidin-4- RTyl]-4-methyl-2,4,5,7-tetrahydro- 18   pyrazolo[3,4-d]pyrimidin-6-oneIa-69 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-15 — E 1.24 (I)534.32 yl]-2-cyclopropyl-7-(2-cyclopropyl-benzyl)- RT4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 18   d]pyrimidin-6-one Ia-702-Cyclopropyl-5-(2′-methoxy-4′-methyl- E-6-16 — E 1.16 (I) 555.353,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- RT4-methyl-7-(2-trifluoromethyl-benzyl)- 18  2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one Ia-715-(4′-Difluoromethyl-2′-methoxy-3,4,5,6- E-6-17 — E 1.21 (I) 565.26tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4- RTdimethyl-7-(2-trifluoromethyl-benzyl)- 16  2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one Ia-725-[1-(2-Difluoromethyl-6-fluoro-phenyl)- E-6-18 — E 1.25 (I) 622.35piperidin-4-yl]-4-methyl-2-(tetrahydro- RTpyran-2-yl)-7-(2-trifluoromethyl-benzyl)- 18  2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (mixture ofdiastereoisomers) (Example 341) Ia-735-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-19 — E 1.27 (I) 606.26yl]-4-methyl-2-(tetrahydro-pyran-2-yl)-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 72  pyrazolo[3,4-d]pyrimidin-6-one (mixture of diastereoisomers) (Example342) Ia-74 5-(4′-Difluoromethyl-2′-methoxy-3,4,5,6- E-6-20 — E 1.26 (I)635.34 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4- RTmethyl-2-(tetrahydro-pyran-2-yl)-7-(2- 72  trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (mixture of diastereoisomers) (Example343) Ia-75 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-6-21 — E 1.12(I) 517.27 yl]-2,4-dimethyl-7-(3-trifluoromethyl-pyridin- RT2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 18   d]pyrimidin-6-oneIa-76 5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- E-6-22 — E 1.01 (I)530.12 2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(3- RTtrifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-772-Cyclopropyl-5-(4′-difluoromethyl-2′- E-6-23 — E 1.23 (I) 591.28methoxy-3,4,5,6-tetrahydro-2H- RT [1,3′]bipyridinyl-4-yl)-4-methyl-7-(2-18   trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-785-[1-(2-Bromo-6-fluoro-phenyl)-piperidin-4- E-6-24 — E 1.26 (I) 606.19yl]-2-cydopropyl-4-methyl-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one Ia-795-(2′-Methoxy-4′-trifluoromethyl-3,4,5,6- E-6-25 — E 1.24 (I) 583.25tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4- RTdimethyl-7-(2-trifluoromethyl-benzyl)- 18  2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one Ia-807-(2-Cyclopropyl-benzyl)-5-(2′-methoxy-4′- E-6-26 — E 1.11 (I) 501.29methyl-3,4,5,6-tetrahydro-2H- RT[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-817-(2-Cyclopropyl-benzyl)-5-(4′- E-6-27 — E 1.19 (I) 537.25difluoromethyl-2′-methoxy-3,4,5,6- RTtetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4- 72  dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one Ia-827-(2-Cydopropyl-benzyl)-5-(4′- E-6-28 — E 1.24 (I) 607.35difluoromethyl-2′-methoxy-3,4,5,6- RTtetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4- 18  methyl-2-(tetrahydro-pyran-2-yl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (mixture of diastereoisomers)(Example 364) Ia-83 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-29— E 1.25 (I) 578.16 yl]-7-(2-cyclopropyl-benzyl)-4-methyl-2- RT(tetrahydro-pyran-2-yl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one (mixture of diastereoisomers) (Example365) Ia-84 7-(2-Cyclopropyl-benzyl)-5-(2′-methoxy-4′- E-6-30 — E 1.23(I) 555.33 trifluoromethyl-3,4,5,6-tetrahydro-2H- RT[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-855-(4′-Chloro-2′-methoxy-3,4,5,6-tetrahydro- E-6-31 — E 1.19 (I) 549.262H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one Ia-865-(4′-Chloro-2′-methoxy-3,4,5,6-tetrahydro- E-6-32 — E 1.19 (I) 521.292H-[1,3′]bipyridinyl-4-yl)-7-(2-cyclopropyl- RTbenzyl)-2,4-dimethyl-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one Ia-872-Cydopropyl-7-(2-cyclopropyl-benzyl)-5- E-6-33 — E 1.15 (I) 527.37(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro- RT2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-882-Cydopropyl-7-(2-cyclopropyl-benzyl)-5- E-6-34 — E 1.22 (I) 563.37(4′-difluoromethyl-2′-methoxy-3,4,5,6- RTtetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4- 18  methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one Ia-895-[1-(2-Bromo-6-fluoro-phenyl)-piperidin-4- E-6-35 — E 1.22 (I) 552.28yl]-7-(2-cyclopropyl-benzyl)-2,4-dimethyl- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 1.5 6-one

Synthesis of Compounds of Formula Ib and Ic Method A (Complete SEMCleavage) Step A (TFA Treatment)

To a soln. of SEM-protected intermediate Ia (1 eq) in DCM (2 to 4mL/mmol) was added dropwise TFA (4 to 6 mL/mmol). The soln. was stirredat RT for a given time (see Table), quenched at 0° C. with a 32% or 1Maq. soln. of NaOH until pH 7-8 and extracted with DCM. The combined org.phases were dried over MgSO₄ and concentrated in vacuo.

Step B (Additional Treatment)

The crude was dissolved in THE (5 to 10 mL/mmol) and treated withethylenediamine (3 eq) for 30 min to 1 h at 60° C. The rxn mixture waspartitioned between DCM and water and the org. phase was washed withbrine, dried over MgSO₄ and concentrated in vacuo. When necessary, thecrude was purified by CC using Hept/EtOAc.

Method B (Partial SEM Cleavage with O-Alkylation) Step A (TFA Treatment)

To a soln. of SEM-protected intermediate Ia (1 eq) in DCM (2 mL/mmol)was added dropwise TFA (4 mL/mmol). The soln. was stirred at RT for agiven time (see Table), quenched at 0° C. with a 32% aq. soln. of NaOHuntil pH 7-8 and extracted with DCM. The combined org. phases were driedover MgSO₄ and concentrated in vacuo.

Step B (Treatment with Alcohol)

The crude was dissolved in EtOH or MeOH (5 mL/mmol) and treated with a4M soln. of HCl in dioxane (5 mL/mmol) for 30 min at 70° C. The rxnmixture was basified with a 1M aq. soln. of NaOH until pH 8-9 andextracted with DCM. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc.

Method C (Bn Cleavage)

To a soln. of Bn-protected intermediate Ia (1 eq) in EtOH (9.8 mL/mmol)was added ammonium formate (4 eq). The flask was evacuated three timesand refilled with nitrogen. 10% Pd/C moistened with ˜50% water (0.1 eq)was added and the flask was evacuated and refilled with hydrogen. Therxn mixture was hydrogenated under atmospheric pressure at a giventemperature for a given time (see Table). When necessary to reachcompletion of the rxn, extra amounts of ammonium formate (4 eq) and/or10% Pd/C moistened with ˜50% water (0.1 eq) were added. The rxn mixturewas filtered over a pad of celite and the filtrate was concentrated invacuo. The crude was purified by CC using Hept/EtOAc.

Method D (THP Cleavage)

To a soln. of THP-protected intermediate Ia (1 eq) in DM (4 to 5mL/mmol) was added dropwise TFA (2 to 4 m/mmol). The soln. was stirredat RT for a given time (see Table), quenched at 0° C. with a 1 M aq.soln. of NaOH until pH 10-11 and extracted with DCM. The combined org.phases were dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc or by prep. LC-MS using method 2, 5 or11.

TABLE 57 Method t_(R) [min] MS-data Reactant T [° C.] (LC/MS m/z Ib orIc Name Ia time [h] method) [M + H]⁺ Ib-16-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4- Ia-1A A 1.15 (I)488.22 (2-trifluoromethyl-benzyl)-1,4,6,7-tetrahydro- or RTpyrazolo[4,3-d]pyrimidin-5-one Ia-1B 2   or6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 2) Ib-25-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- Ia-2 A 1.14 (I)488.24 (2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- RTpyrazolo[3,4-d]pyrimidin-6-one 2.5 (Example 6) Ic-12-Ethoxymethyl-5-[1-(2-fluoro-6-methyl-phenyl)- Ia-2 B (EtOH)  1.08 (II)546.02 piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6- 1   one (Example 7) Ib-31-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-3- Ia-5 A (only  0.91(II) 488.11 (2-trifluoromethyl-benzyl)-1,3,6,9-tetrahydro- step A)purin-2-one RT (Example 14) 4.5 Ib-46-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4- Ia-12 C  1.02 (II)489.10 (2-trifluoromethyl-benzyl)-3,4,6,7-tetrahydro- 60  [1,2,3]triazolo[4,5-d]pyrimidin-5-one 48   or6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5-one (Example 76) Ib-55-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- Ia-19 A 1.04 (I)489.22 (3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7- RTtetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 0.7 (Example 193) Ib-65-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H- Ia-20 A 1.03 (I) 501.24[1,3′]bipyridinyl-4-yl)-7-(2-trifluoromethyl-benzyl)- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6- 1   one (Example 197)Ib-7 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4- Ia-21 A 1.04 (I)489.22 (3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7- RTtetrahydro-pyrazolo[4,3-d]pyrimidin-5-one 2   (Example 204) Ib-87-(2-Bromo-6-trifluoromethyl-benzyl)-5-[1-(2- Ia-23 A 1.16 (I) 566.11fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,4,5,7- RTtetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 0.5 (Example 211) Ib-96-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H- Ia-24 A 1.03 (I) 501.22[1,3′]bipyridinyl-4-yl)-4-(2-trifluoromethyl-benzyl)- RT2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5- 2   one (Example 218)Ic-92 2-Methoxymethyl-5-(2′-methoxy-4′-methyl- Ia-20 B  1.21 (IV) 544.803,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2- (MeOH)trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- RTpyrazolo[3,4-d]pyrimidin-6-one (Example 227) 1   Ib-106-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- Ia-35 A 1.16 (I)502.18 methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7- RTtetrahydro-pyrazolo[4,3-d]pyrimidin-5-one 1   Ib-114-(2-Cyclopropyl-benzyl)-6-(2′-methoxy-4′- Ia-48 D 1.02 (I) 487.25methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4- RTyl)-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3- 20   d]pyrimidin-5-oneIb-12 4-(2-Cyclopropyl-benzyl)-6-[1-(2-fluoro-6-methyl- Ia-47 D 1.13 (I)474.29 phenyl)-piperidin-4-yl]-7-methyl-2,4,6,7- RTtetrahydro-pyrazolo[4,3-d]pyrimidin-5-one 20   Ib-135-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4- Ia-51 D 1.14 (I)502.33 methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7- RTtetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 20   Ib-146-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H- Ia-53 D 1.03 (I) 515.31[1,3′]bipyridinyl-4-yl)-7-methyl-4-(2- RTtrifluoromethyl-benzyl)-2,4,6,7-tetrahydro- 2  pyrazolo[4,3-d]pyrimidin-5-one Ib-156-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7- Ia-63 D 1.17 (I)522.19 methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7- RTtetrahydro-pyrazolo[4,3-d]pyrimidin-5-one 1.5 Ib-166-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin- Ia-64 D 1.16 (I)538.21 4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)- RT2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5- 1.5 one Ib-175-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin- Ia-72 D 1.15 (I)538.19 4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)- RT2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6- 18   one Ib-185-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-4- Ia-73 D 1.16 (I)522.17 methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7- RTtetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 18   Ib-195-(4′-Difluoromethyl-2′-methoxy-3,4,5,6- Ia-74 D 1.14 (I) 551.23tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-7- RT(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one Ib-207-(2-Cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′- Ia-82 D 1.12 (I)523.30 methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl- RT4-yl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 3   d]pyrimidin-6-oneIb-21 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7- Ia-83 D 1.15(I) 494.22 (2-cyclopropyl-benzyl)-4-methyl-2,4,5,7- RTtetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 6  

Synthesis of Compounds of Formula Ic, Id and Ie Method A (MethylationUsing Silver Carbonate)

To a suspension of intermediate Ib (1 eq) and silver carbonate (1.2 eq)in toluene (6 mL/mmol) was added Mel (5 eq) and the rxn mixture wasstirred at 85° C. for a given time (see Table). It was filtered and thefiltrate was concentrated in vacuo. The crude was purified by CC usingDCM/MeOH. When necessary, an additional purification by prep. LC-MSusing methods 1, 3 or 4 was performed.

Method B (Alkylation Using NaH and Halide or Aziridine)

Method B1: A soln. or suspension of intermediate Ib (1 eq) in anh. THE(6 to 10 mL/mmol) was added dropwise at 0° C. to a suspension of NaH(2.2 to 4 eq, as a 60% dispersion in mineral oil) in anh. THE (4 to 6mL/mmol).

Method B2: NaH (4 eq, as a 60% dispersion in mineral oil) was addedportionwise at 0° C. to a soln. or suspension of intermediate Ib (1 eq)in THE (10 to 13 mL/mmol).

Common following procedure: The suspension was stirred for 10 to 30 minat RT, cooled to 0° C. and halide or aziridine BB-10 (1.2 to 3 eq) wasadded. The rxn mixture was stirred at a given temperature for a giventime (see Table). When necessary to reach completion of the rxn, extraamounts of NaH (1 to 2 eq) and/or halide or aziridine BB-10 (1 eq) wereadded. The rxn mixture was quenched with H₂O at 0° C. and extracted withEtOAc or DCM. The combined org. phases were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc and/or DCM/MeOH.

Method C (Alkylation Using Mitsunobu Conditions)

To a soln. or suspension of intermediate Ib (1 eq) and alcohol BB-10(1.5 to 2 eq) in toluene (6 to 12 mL/mmol) was added a 1M soln. of(tributylphosphoranylidene)acetonitrile in toluene (2 eq) under argon.The rxn mixture was heated to a given temperature and stirred for agiven time (see Table). It was quenched with water and extracted withEtOAc or DCM. The combined org. phases were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc or DCM/MeOH. When necessary, an additional purification byprep. LC-MS using methods 2, 4, 5, 8 or 10 was performed.

Method D (Methylation Using DBU)

To a soln. of intermediate Ib (1 eq) and DBU (1.2 eq) in anh. DMF (4mL/mmol) was added Mel (1.3 eq). The rxn mixture was stirred at RT for agiven time (see Table) and evaporated under reduced pressure. Theresidue was purified by prep. LC-MS using methods 2, 4 and/or 5.

Method E (Alkylation Using K₂CO₃ and Halide or Epoxide)

A mixture of compound Ib (1 eq), K₂CO₃ (1.5 to 5 eq) and epoxide orhalide BB-10 (2 to 5 eq) in DMF (5 to 8.5 mL/mmol) was heated to a giventemperature and stirred for a given time (see Table). When necessary toreach completion of the rxn an extra amount of epoxide or halide BB-10(1 eq) was added and the rxn mixture was further stirred for 2 h at 120°C. It was partitioned between EtOAc and H₂O and the org. phase waswashed with H₂O and brine, dried over MgSO₄ and concentrated in vacuo.The crude was purified by CC using Hept/EtOAc.

Method F (1,4-Nucleophilic Addition Using K₂CO₃)

A mixture of compound Ib (1 eq), α,β-unsaturated carbonyl reagent BB-10(2 eq), K₂CO₃ (1.5 eq) and TEA (3 eq) in THE (10 mL/mmol) was heated to60° C. and stirred for a given time (see Table). It was partitionedbetween DCM and H₂O and the org. phase was washed with brine, dried overMgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc.

Method G (1,4-Nucleophilic Addition Using CsF)

To a soln. of compound Ib (1 eq) in DMF (10 mL/mmol) was addednitroalkene BB-10 (1 eq) and CsF (1.2 eq) at 0° C. The rxn mixture wasstirred for 30 min at 0° C. and at RT for a given time (see Table).Consecutive additions of BB-10 (1 eq) and CsF (1 eq) at 0° C. werenecessary to allow the rxn to proceed. It was partitioned between EtOAcand H₂O and the org. phase was washed with H₂O and brine, dried overMgSO₄ and concentrated in vacuo. The crude was purified by prep LC-MSusing method 4.

Method H (Alkoxycarbonylation/Alkylcarbamylation)

A soln. of compound Ib (1 eq) and TEA (3 eq) in DCM (8.1 mL/mmol) wascooled to 0° C. and chloroformate or isocyanate BB-10 (2 eq) was addeddropwise at 0° C. The rxn mixture was allowed to slowly reach RT andstirred for a given time (see Table). It was diluted with DCM and washedwith a sat. aq. soln. of NaHCO₃ and with brine. The org. phase was driedover MgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc.

Method I (Urea Formation)

A soln. of compound Ib (1 eq) and TEA (3 eq) in THE (10 mL/mmol) wastreated with CDI (1.2 eq) and the rxn mixture was stirred at RT for 15min. Amine BB-10 (3 to 5 eq) was added at RT and the mixture was stirredat a given temperature for a given time (see Table). The rxn mixture waspartitioned between DCM and a half sat. aq. soln. of NaHCO₃ and the org.phase was washed with brine, dried over MgSO₄ and concentrated in vacuo.The crude was purified by CC using Hept/EtOAc.

Method J1 (Chan-Lam Rxn 1)

A mixture of compound Ib (1 eq), boron species BB-10 (2 eq), Na₂CO₃ (2eq), 2,2′-bipyridyl (1 eq) and Cu(OAc)₂ (1 eq) in toluene (10 to 12mL/mmol) was flushed with N₂ and heated at a given temperature for agiven time (see Table). When necessary to reach completion of the rxn anextra amount of boron species BB-10 (2 eq) was added. It was partitionedbetween EtOAc or DCM and a sat. aq. soln. of NaHCO₃ and the org. phasewas washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using Hept/EtOAc or DCM/MeOH and/or by prep.HPLC using method 3 or 5.

Method J2 (Chan-Lam Rxn 2)

suspension of 2,2′-bipyridyl (1 eq) and Cu(OAc)₂ (1 eq) intrifluorobenzene (3 mL/mmol) was heated to 70° C. and stirred for 30 mm.It was added at RT to a mixture of compound Ib (1 eq), boron speciesBB-10 (2 eq) and Na₂CO₃ (2 eq) in trifluoromethylbenzene (1.5 mL/mmol).The rxn mixture was heated to 110° C. and stirred for a given time (seeTable). It was diluted with EtOAc and washed with a 10% soln. of citricacid. The org. phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by prep. LC-MS usingmethod 4.

Method K (Alkylation Using Cs₂CO₃ and Tosylate)

A mixture of compound Ib (1 eq), tosylate BB-10 (1.05 to 1.5 eq) andCs₂CO₃ (2 to 2.3 eq) in DMA (5 to 7 mL/mmol) was heated at a giventemperature for a given time (see Table). It was partitioned betweenEtOAc and water and the org. phase was washed with brine, dried overMgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc or/and by prep. LC-MS using method 4 or 5.

TABLE 60 Method t_(R) [min] MS-data Reactant Reactant T [° C.] (LC/MS-m/z Ic/Id/Ie Name Ib BB-10 time [h] method) [M + H]⁺ Ic-26-[1-(2-Fluoro-6-methyl-phenyl)- Ib-1  MeI A 1.08 502.27piperidin-4-yl]-2-methyl-4-(2- 85  (II) trifluoromethyl-benzyl)-2,4,6,7- 0.25 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 3) Id-16-[1-(2-Fluoro-6-methyl-phenyl)- 1.07 502.70piperidin-4-yl]-1-methyl-4-(2- (II) trifluoromethyl-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 4) Ic-35-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  MeI B1 1.22 502.16piperidin-4-yl]-2-methyl-7-(2- RT (I) trifluoromethyl-benzyl)-2,4,5,7-1.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 8) Ic-45-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  CD₃OD C 1.20 505.27piperidin-4-yl]-2-[²H₃]methyl-7-(2- 110   (I)trifluoromethyl-benzyl)-2,4,5,7- 1  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 9) Ie-1 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  MeI A 1.11502.10 piperidin-4-yl]-1-methyl-7-(2- 85  (II)trifluoromethyl-benzyl)-1,4,5,7- 3  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 10) Id-2 1-[1-(2-Fluoro-6-methyl-phenyl)- Ib-3  MeI D0.99 502.11 piperidin-4-yl]-7-methyl-3-(2- RT (II)trifluoromethyl-benzyl)-1,3,6,7- 18  tetrahydro-purin-2-one (Example 16)Ic-5 [5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Bromoacetic acid B1 1.05560.09 piperidin-4-yl]-6-oxo-7-(2- methyl ester RT (II)trifluoromethyl-benzyl)-4,5,6,7- 1.5tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-acetic acid methyl ester(Example 17) Ic-6 [6-[1-(2-Fluoro-6-methyl-phenyl)- Ib-1  Bromoaceticacid B1 1.04 560.19 piperidin-4-yl]-5-oxo-4-(2- methyl ester RT (II)trifluoromethyl-benzyl)-4,5,6,7- 4  tetrahydro-pyrazolo[4,3-d]pyrimidin-2-yl]-acetic acid methyl ester (Example 18) Id-3[6-[1-(2-Fluoro-6-methyl-phenyl)- 1.04 560.19piperidin-4-yl]-5-oxo-4-(2- (II) trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 1-yl]-acetic acid methyl ester(Example 19) Ic-8 [5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Bromo B1 1.04527.12 piperidin-4-yl]-6-oxo-7-(2- acetonitrile RT (II)trifluoromethyl-benzyl)-4,5,6,7-  0.25tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-acetonitrile (Example 24)Ic-9 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2,2-Dimethyl E 1.18 560.16piperidin-4-yl]-2-(2-hydroxy-2- oxirane 100   (I)methyl-propyl)-7-(2-trifluoromethyl- 18  benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 25) Ic-102-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Bromo-2-methyl B1 1.10588.08 piperidin-4-yl]-6-oxo-7-(2- propanoic acid 60  (II)trifluoromethyl-benzyl)-4,5,6,7- methyl ester 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-2-methyl-propionic acidmethyl ester (Example 27) Ic-11 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- 1.09588.12 piperidin-4-yl]-6-oxo-7-(2- (II) trifluoromethyl-benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-2-methyl-propionic acidmethyl ester (Example 31) Ic-12 2-(2,2-Diethoxy-ethyl)-5-[1-(2-fluoro-Ib-2  Bromo B1 1.11 604.06 6-methyl-phenyl)-piperidin-4-yl]-7-acetaldehyde 70  (II) (2-trifluoromethyl-benzyl)-2,4,5,7- diethyl acetal192   tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 28) Ic-132-(2,3-Dihydroxy-propyl)-5-[1-(2- Ib-2  Oxiran-2-yl E 0.95 561.98fluoro-6-methyl-phenyl)-piperidin-4- methanol 100   (II)yl]-7-(2-trifluoromethyl-benzyl)- 1  2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 40) Ic-14 5-[1-(2-Fluoro-6-methyl-phenyl)-Ib-2  (S)-2-(Methoxy E 1.02 576.10 piperidin-4-yl]-2-((R)-2-hydroxy-3-methyl)oxirane 100   (II) methoxy-propyl)-7-(2- 5 trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 41) Ic-15 2-Chloro-3-[5-[1-(2-fluoro-6-methyl- Ib-2 2-Chloro acrylic F 1.09 608.01 phenyl)-piperidin-4-yl]-6-oxo-7-(2- acidmethyl ester 60  (II) trifluoromethyl-benzyl)-4,5,6,7- 24 tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-propionic acid methyl ester(Example 42) Ic-16 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2 2-Chloro-2-methyl E 1.07 555.12 piperidin-4-yl]-6-oxo-7-(2-propanenitrile 100   (II) trifluoromethyl-benzyl)-4,5,6,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-2-methyl-propionitrile(Example 43) Ic-17 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  (R)-2-(methoxyE 1.02 576.11 piperidin-4-yl]-2-((S)-2-hydroxy-3- methyl)oxirane 100(II) methoxy-propyl)-7-(2- 4  trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 46) Ic-182-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Bromo B1 1.01 559.19piperidin-4-yl]-6-oxo-7-(2- propionamide RT (II)trifluoromethyl-benzyl)-4,5,6,7- 2  tetrahydro-pyrazolo[3,4-d]pyrimidin-2-yl]-propionamide (Example 75) Ic-19 5-[1-(2-Fluoro-6-methyl-phenyl)-Ib-2  Oxetan-3-ol C 1.08 544.18 piperidin-4-yl]-2-oxetan-3-yl-7-(2-110   (II) trifluoromethyl-benzyl)-2,4,5,7- 1.5tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 77) Ic-206-[1-(2-Fluoro-6-methyl-phenyl)- Ib-4  MeI B2 1.10 503.15piperidin-4-yl]-2-methyl-4-(2- RT (II) trifluoromethyl-benzyl)-2,4,6,7-2  tetrahydro-[1,2,3]triazolo[4,5- d]pyrimidin-5-one (Example 81) Ic-215-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  1-Nitro-1- G 1.12 615.13piperidin-4-yl]-2-(2-nitro-cyclohexyl)- cyclohexane RT (II)7-(2-trifluoromethyl-benzyl)-2,4,5,7- 72 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 82) Ic-22{2,2,2-Trifluoro-1-[5-[1-(2-fluoro-6- Ib-2  BB-10-1 E 1.14 699.20methyl-phenyl)-piperidin-4-yl]-6-oxo- 80  (II)7-(2-trifluoromethyl-benzyl)-4,5,6,7- 24 tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-1-methyl-ethyl}-carbamic acidtert-butyl ester (Example 83) Ic-23 2-[5-[1-(2-Fluoro-6-methyl-phenyl)-Ib-2 2-Bromo-2-methyl B2 1.04 573.09 piperidin-4-yl]-6-oxo-7-(2-propionamide RT (II) trifluoromethyl-benzyl)-4,5,6,7- 168  tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-isobutyramide (Example 84)Ic-24 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  3-Hydroxy C 1.12 643.17piperidin-4-yl]-6-oxo-7-(2- azetidine-1- 110   (II)trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester2-yl]-azetidine-1-carboxylic acid tert- butyl ester (Example 91) Ic-253-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  3-Hydroxy- C 1.13 657.20piperidin-4-yl]-6-oxo-7-(2- pyrrolidine-1- 110   (II)trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert- 1 tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 93) Ic-262-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Hydroxy methyl- C 1.13657.18 piperidin-4-yl]-6-oxo-7-(2- azetidine-1- 110   (II)trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert- 0.5tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester2-ylmethyl]-azetidine-1-carboxylic acid tert-butyl ester Ic-272-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Hydroxy methyl- C 1.14671.17 piperidin-4-yl]-6-oxo-7-(2- pyrrolidine-1- 110   (II)trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert- 1 tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester2-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 97)Ic-28 {2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  (2-Hydroxy- C 1.14671.21 piperidin-4-yl]-6-oxo-7-(2- cyclopentyl)- 110   (II)trifluoromethyl-benzyl-)-4,5,6,7- carbamic acid tert- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester2-yl]-cyclopentyl}-carbamic acid tert- butyl ester (Example 98) Ic-294-Chloro-N-{2-[5-[1-(2-fluoro-6- Ib-2  BB-10-2 B2 1.13 733.18methyl-phenyl)-piperidin-4-yl]-6-oxo- 70  (II)7-(2-trifluoromethyl-benzyl)-4,5,6,7- 3.5tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-1,1-dimethyl-ethyl}-benzenesulfonamide (Example 101) Ic-30(R)-4,4-Difluoro-2-[5-[1-(2-fluoro-6- Ib-2  (R)-4,4-Difluoro-2- C 1.30707.14 methyl-phenyl)-piperidin-4-yl]-6-oxo- hydroxy methyl- 110   (I)7-(2-trifluoromethyl-benzyl)-4,5,6,7- pyrrolidine-1- 1tetrahydro-pyrazolo[3,4-d]pyrimidin- carboxylic acid tert-2-ylmethyl]-pyrrolidine-1-carboxylic butyl ester acid tert-butyl ester(Example 108) Ic-31 (S)-4,4-Difluoro-2-[5-[1-(2-fluoro-6- Ib-2 (S)-4,4-Difluoro-2- C 1.30 707.16 methyl-phenyl)-piperidin-4-yl]-6-oxo-hydroxy methyl- 110   (I) 7-(2-trifluoromethyl-benzyl)-4,5,6,7-pyrrolidine-1- 1 tetrahydro-pyrazolo[3,4-d]pyrimidin- carboxylic acidtert- 2-ylmethyl]-pyrrolidine-1-carboxylic butyl ester acid tert-butylester (Example 109) Ic-32 N-{2-[5-[1-(2-Fluoro-6-methyl- Ib-2  BB-10-3B2 1.26 744.23 phenyl)-piperidin-4-yl]-6-oxo-7-(2- RT (I)trifluoromethyl-benzyl)-4,5,6,7- 24 tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-1,1-dimethyl-ethyl}-2-nitro-benzenesulfonamide (Example 110) Ic-33 (S)-2-[5-(1-(2-Fluoro-6-methyl-Ib-2  (S)-2-Hydroxy- C 1.28 657.21 phenyl)-piperidin-4-yl]-6-oxo-7-(2-methyl-azetidine-1- 110   (I) trifluoromethyl-benzyl)-4,5,6,7-carboxylic acid tert-  1.25 tetrahydro-pyrazolo[3,4-d]pyrimidin- butylester 2-ylmethyl]-azetidine-1-carboxylic acid tert-butyl ester (Example121) Ic-34 (R)-2-[5-[1-(2-Fluoro-6-methyl- Ib-2  (R)-2-Hydroxy C 1.30657.22 phenyl)-piperidin-4-yl]-6-oxo-7-(2- methyl-azetidine-1- 110   (I)trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert- 1.5tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester2-ylmethyl]-azetidine-1-carboxylic acid tert-butyl ester (Example 129)Ic-35 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Isopropyl H 1.27 574.10piperidin-4-yl]-6-oxo-7-(2- chloroformate (1M RT (I)trifluoromethyl-benzyl)-4,5,6,7- soln. In toluene) 1 tetrahydro-pyrazolo[3,4- d]pyrimidine-2-carboxylic acid isopropyl ester(Example 147) Ic-36 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Isobutyl H1.30 588.12 piperidin-4-yl]-6-oxo-7-(2- chloroformate RT (I)trifluoromethyl-benzyl)-4,5,6,7- 1.5 tetrahydro-pyrazolo[3,4-d]pyrimidine-2-carboxylic acid isobutyl ester (Example 148) Ic-375-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Dimethylamine (2M I 1.25 559.11piperidin-4-yl]-6-oxo-7-(2- soln. in THF) RT (I)trifluoromethyl-benzyl)-4,5,6,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidine-2-carboxylic acid dimethylamide (Example 149) Ic-385-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Isobutyl-methyl- I 1.32 601.11piperidin-4-yl]-6-oxo-7-(2- amine RT (I)trifluoromethyl-benzyl)-4,5,6,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidine-2-carboxylic acid isobutyl-methyl-amide (Example 150) Ic-395-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  3-Bromo-1- B2 1.17 585.20piperidin-4-yl]-2-(1-methyl-2-oxo- methylpyrrolidin-2- RT (I)pyrrolidin-3-yl)-7-(2-trifluoromethyl- one 0.5benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 151)Ic-40 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  3-Bromo-1-(propan- B2 1.22613.24 piperidin-4-yl]-2-(1-isopropyl-2-oxo- 2-yl)pyrrolidin-2- RT (I)pyrrolidin-3-yl)-7-(2-trifluoromethyl- one 0.5benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 152)Ic-41 5-[1-(2-Fluoro-6-methyl-phenyl)- piperidin-4-yl]-2-[2-([²H₃]methyl)[1,1,2,3,3,3-²H₆]propyl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 156) Ib-2 

C 110   2.5 1.27 (I) 553.24 Ic-42 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2 BB-10-4 E 1.35 799.16 piperidin-4-yl]-2-(2-oxo-1-trityl- 150   (I)azetidin-3-yl)-7-(2-trifluoromethyl- 1.5 benzyl)-2,4,5,7-tetrahydro-(microwave) pyrazolo[3,4-d]pyrimidin-6-one Ic-435-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  (1-Methyl- C 1.28 556.14piperidin-4-yl]-2-(1-methyl- cyclopropyl)- 110   (I)cyclopropylmethyl)-7-(2- methanol 1 trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 158) Ic-442-(2,2-Difluoro-ethyl)-5-[1-(2-fluoro- Ib-2  2,2-Difluoroethanol C 1.21552.07 6-methyl-phenyl)-piperidin-4-yl]-7- 110   (I)(2-trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 159) Ic-452-(1,1-Dimethyl-prop-2-ynyl)-5-[1- Ib-2  2-Methyl-3-butyn-2- C 1.28554.13 (2-fluoro-6-methyl-phenyl)-piperidin- ol 110   (I)4-yl]-7-(2-trifluoromethyl-benzyl)- 18  2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 160) Ic-46 5-[1-(2-Fluoro-6-methyl-phenyl)-Ib-2  2-Propanol C 1.26 530.12 piperidin-4-yl]-2-isopropyl-7-(2- 110  (I) trifluoromethyl-benzyl)-2,4,5,7- 1 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 161) Ic-475-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-[1,1,1,2,3,3,3- C 1.26 537.31piperidin-4-yl]-2-([1,1,1,2,3,3,3- ²H₇]Propan[²H]ol 110   (I)²H₇]propan-2-yl)-7-(2- 1.5 trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 162) Ic-485-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-[1,1,1,3,3,3- C 1.26 536.30piperidin-4-yl]-2-([1,1,1,3,3,3- ²H₆]Propanol 110   (I)²H₆]propan-2-yl)-7-(2- 1.5 trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 163) Ic-495-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  (3-Fluoro-oxetan-3- C 1.20 576.12piperidin-4-yl]-2-(3-fluoro-oxetan-3- yl)-methanol 110   (I)ylmethyl)-7-(2-trifluoromethyl- 1.5 benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 164) Ic-502-Cyclopropylmethyl-5-[1-(2-fluoro- Ib-2  Cyclopropyl- C 1.26 542.096-methyl-phenyl)-piperidin-4-yl]-7- methanol 110   (I)(2-trifluoromethyl-benzyl)-2,4,5,7- 1 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 165) Ie-21-Cyclopropylmethyl-5-[1-(2-fluoro- 1.24 542.306-methyl-phenyl)-piperidin-4-yl]-7- (I)(2-trifluoromethyl-benzyl)-1,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 210) Ic-52 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2 (3-Methyl-oxetan-3- C 1.23 572.12 piperidin-4-yl]-2-(3-methyl-oxetan-3-yl)-methanol 110   (I) ylmethyl)-7-(2-trifluoromethyl- 1 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 166)Ic-53 2-(1-Fluoro-cyclopropylmethyl)-5-[1- Ib-2  (1-Fluoro- C 1.25560.22 (2-fluoro-6-methyl-phenyl)-piperidin- cyclopropyl)- 110   (I)4-yl]-7-(2-trifluoromethyl-benzyl)- methanol 2 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 167) Ic-545-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Fluoro-2- C 1.27 562.23piperidin-4-yl]-2-(2-fluoro-2-methyl- methylpropan-1-ol 110   (I)propyl)-7-(2-trifluoromethyl-benzyl)- 2 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 168) Ic-552-Ethyl-5-[1-(2-fluoro-6-methyl- Ib-2  Ethanol C 1.23 516.03phenyl)-piperidin-4-yl]-7-(2- 110   (I) trifluoromethyl-benzyl)-2,4,5,7-1  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 169) Ic-562-[1,1,2,2,2-²H₅]Ethyl-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- (2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 170) Ib-2 

C 110   2  1.24 (I) 521.27 Ic-57 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2 3-Hydroxy methyl- C 1.12 574.22 piperidin-4-yl]-2-(3-hydroxy-oxetan-oxetan-3-ol 110   (I) 3-ylmethyl)-7-(2-trifluoromethyl- 1 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 171)Ic-58 2-(2,2-Difluoro-propyl)-5-[1-(2- Ib-2  2,2-Difluoro C 1.24 566.14fluoro-6-methyl-phenyl)-piperidin-4- propanol 110   (I)yl]-7-(2-trifluoromethyl-benzyl)- 5  2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 172) Ic-592-tert-Butyl-5-[1-(2-fluoro-6-methyl- Ib-2  tert-Butanol C 1.30 544.29phenyl)-piperidin-4-yl]-7-(2- 110   (I) trifluoromethyl-benzyl)-2,4,5,7-18  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 173) Ic-602-Cyclopropyl-5-[1-(2-fluoro-6- Ib-2  Cyclopropyl boronic J 1.22 528.26methyl-phenyl)-piperidin-4-yl]-7-(2- acid 70  (I)trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 174) Ic-612-Cyclopropyl-6-[1-(2-fluoro-6- Ib-1  Cyclopropyl boronic J 1.22 528.17methyl-phenyl)-piperidin-4-yl]-4-(2- acid 90  (I)trifluoromethyl-benzyl)-2,4,6,7- 18 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 175) Ic-626-[1-(2-Fluoro-6-methyl-phenyl)- Ib-1  2-Fluoro-2- C 1.22 562.14piperidin-4-yl]-2-(2-fluoro-2-methyl- methylpropan-1-ol 100   (I)propyl)-4-(2-trifluoromethyl-benzyl)- 2 2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Example 176) Id-46-[1-(2-Fluoro-6-methyl-phenyl)- 1.22 562.13piperidin-4-yl]-1-(2-fluoro-2-methyl- (I)propyl)-4-(2-trifluoromethyl-benzyl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 177) Ic-642-Cyclopropylmethyl-6-[1-(2-fluoro- Ib-1  Cyclopropyl C 1.24 542.286-methyl-phenyl)-piperidin-4-yl]-4- methanol 100   (I)(2-trifluoromethyl-benzyl)-2,4,6,7- 1 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 178) Id-51-Cyclopropylmethyl-6-[1-(2-fluoro- 1.23 542.276-methyl-phenyl)-piperidin-4-yl]-4- (I)(2-trifluoromethyl-benzyl)-1,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 179) Ic-66 6-[1-(2-Fluoro-6-methyl-phenyl)- Ib-1 (1-Methyl- C 1.25 556.20 piperidin-4-yl]-2-(1-methyl- cyclopropyl)-100   (I) cyclopropylmethyl)-4-(2- methanol 1 trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 180) Id-6 6-[1-(2-Fluoro-6-methyl-phenyl)- 1.24 556.20piperidin-4-yl]-1-(1-methyl- (I) cyclopropylmethyl)-4-(2-trifluoromethyl-benzyl)-1,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 181) Ic-68 2-Ethyl-6-[1-(2-fluoro-6-methyl- Ib-1  EthanolC 1.22 516.26 phenyl)-piperidin-4-yl]-4-(2- 100   (I)trifluoromethyl-benzyl)-2,4,6,7- 1  tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 182) Ic-69 2-tert-Butyl-6-[1-(2-fluoro-6-methyl- Ib-1 tert-Butanol C 1.26 544.30 phenyl)-piperidin-4-yl]-4-(2- 100   (I)trifluoromethyl-benzyl)-2,4,6,7- 48 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 183) Ic-702-(1-Fluoro-cyclopropylmethyl)-6-[1- Ib-1  (1-Fluoro- C 1.21 560.26(2-fluoro-6-methyl-phenyl)-piperidin- cyclopropyl)- 100   (I)4-yl]-4-(2-trifluoromethyl-benzyl)- methanol 1 2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Example 184) Ic-715-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Fluoro C 1.22 548.15piperidin-4-yl]-2-(2-fluoro-propyl)-7- propan-1-ol 100   (I)(2-trifluoromethyl-benzyl)-2,4,5,7- 2.5tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one Ic-722-(2,2-Difluoro-1-methyl-ethyl)-5-[1- Ib-2  1,1-Difluoro C 1.23 566.13(2-fluoro-6-methyl-phenyl)-piperidin- propan-2-ol 100   (I)4-yl]-7-(2-trifluoromethyl-benzyl)- 18  2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ic-73 2-(2,2-Difluoro-cyclopropylmethyl)- Ib-2 (2,2-Difluoro- C 1.24 578.23 5-[1-(2-fluoro-6-methyl-phenyl)-cyclopropyl)- 100   (I) piperidin-4-yl]-7-(2-trifluoromethyl- methanol2.5 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one Ic-746-[1-(2-Fluoro-6-methyl-phenyl)- Ib-1  2-Isopropenyl- J 1.26 528.23piperidin-4-yl]-2-isopropenyl-4-(2- 4,4,5,5-tetramethyl- 70  (I)trifluoromethyl-benzyl)-2,4,6,7- [1,3,2]dioxaborolane 18 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 192) Ic-752-(2,2-Difluoro-propyl)-5-[1-(2- Ib-5  2,2-Difluoro C 1.17 567.25fluoro-6-methyl-phenyl)-piperidin-4- propanol 110   (I)yl]-7-(3-trifluoromethyl-pyridin-2- 4  ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 194) Ic-762-(2,2-Difluoro-propyl)-6-[1-(2- Ib-1  2,2-Difluoro C 1.20 566.02fluoro-6-methyl-phenyl)-piperidin-4- propanol 110   (I)yl]-4-(2-trifluoromethyl-benzyl)- 20  2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 198) Ic-772-(1-Fluoro-cyclopropylmethyl)-5-[1- Ib-5  (1-Fluoro- C 1.16 561.12(2-fluoro-6-methyl-phenyl)-piperidin- cyclopropyl)- 110   (I)4-yl]-7-(3-trifluoromethyl-pyridin-2- methanol 2 ylmethyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example200) Ic-78 2-(1-Fluoro-cyclopropylmethyl)-5- Ib-6  (1-Fluoro- C 1.16573.27 (2′-methoxy-4′-methyl-3,4,5,6- cyclopropyl)- 110   (I)tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- methanol 2.57-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 201) Ic-792-(2,2-Difluoro-propyl)-5-(2′- Ib-6  2,2-Difluoro C 1.17 579.29methoxy-4′-methyl-3,4,5,6- propanol 110   (I)tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 18 7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 205) Ic-802-Cyclopropyl-5-[1-(2-fluoro-6- Ib-5  Cyclopropyl boronic J 1.17 529.17methyl-phenyl)-piperidin-4-yl]-7-(3- acid 70  (I)trifluoromethyl-pyridin-2-ylmethyl)- 18 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-5-one (Example 206) Ic-812-(2,2-Difluoro-propyl)-6-[1-(2- Ib-7  2,2-Difluoro C 1.13 567.23fluoro-6-methyl-phenyl)-piperidin-4- propanol 100   (I)yl]-4-(3-trifluoromethyl-pyridin-2- 18  ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 207) Ic-822-(1-Fluoro-cyclopropylmethyl)-6-[1- Ib-7  (1-Fluoro- C 1.14 561.21(2-fluoro-6-methyl-phenyl)-piperidin- cyclopropyl)- 100   (I)4-yl]-4-(3-trifluoromethyl-pyridin-2- methanol 1 ylmethyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Example208) Ic-83 2-Cyclopropyl-5-(2′-methoxy-4′- Ib-6  Cyclopropyl boronic J1.17 541.22 methyl-3,4,5,6-tetrahydro-2H- acid 70  (I)[1,3′]bipyridinyl-4-yl)-7-(2- 18  trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 209) Ic-842-Cyclopropyl-6-[1-(2-fluoro-6- Ib-7  Cyclopropyl boronic J 1.13 529.13methyl-phenyl)-piperidin-4-yl]-4-(3- acid 70  (I)trifluoromethyl-pyridin-2-ylmethyl)- 3.52,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Example 212) Id-71-Cyclopropyl-6-[1-(2-fluoro-6 1.13 529.08methyl-phenyl)-piperidin-4-yl]-4-(3- (I)trifluoromethyl-pyridin-2-ylmethyl)- 1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 215) Ic-86 7-(2-Bromo-6-trifluoromethyl-Ib-8  Cyclopropyl boronic J 1.24 606.10benzyl)-2-cyclopropyl-5-[1-(2-fluoro- acid 70  (I)6-methyl-phenyl)-piperidin-4-yl]- 2  2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 213) Ic-87 7-(2-Bromo-6-trifluoromethyl-Ib-8  2,2-Difluoro C 1.23 643.87 benzyl)-2-(2,2-difluoro-propyl)-5-[1-propanol 100   (I) (2-fluoro-6-methyl-phenyl)-piperidin- 3 4-yl]-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 214)Ic-88 2-(2,2-Difluoro-propyl)-6-(2′- Ib-9  2,2-Difluoro C 1.13 579.24methoxy-4′-methyl-3,4,5,6- propanol 100   (I)tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 48 4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 219) Ic-892-(1-Fluoro-cyclopropylmethyl)-6- Ib-9  (1-Fluoro- C 1.13 573.27(2′-methoxy-4′-methyl-3,4,5,6- cyclopropyl)- 110   (I)tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- methanol 2.54-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 222) Ic-902-Cyclopropyl-6-(2′-methoxy-4′- Ib-9  Cyclopropyl boronic J 1.14 541.28methyl-3,4,5,6-tetrahydro-2H- acid 70  (I) [1,3′]bipyridinyl-4-yl)-4-(2-4  trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 223) Ic-91 6-(2′-Methoxy-4′-methyl-3,4,5,6- Ib-9  Methyl4- K 1.11 515.26 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- toluenesulfonate100   (I) 2-methyl-4-(2-trifluoromethyl- 3  benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 224) Id-82-(2,2-Difluoro-propyl)-6-[1-(2- Ib-7  2,2-Difluoropropyl K 1.14 567.20fluoro-6-methyl-phenyl)-piperidin-4- 4-methyl benzene 60  (I)yl]-4-(3-trifluoromethyl-pyridin-2- sulfonate 18 ylmethyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Example239) Ic-93 2-(2,2-Difluoro-propyl)-6-[1-(2- Ib-10 2,2-Difluoropropyl K1.21 580.23 fluoro-6-methyl-phenyl)-piperidin-4- 4-methyl benzene 100  (I) yl]-7-methyl-4-(2-trifluoromethyl- sulfonate 2 benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one Id-91-(2,2-Difluoro-propyl)-6-[1-(2- 1.20 580.22fluoro-6-methyl-phenyl)-piperidin-4- (I)yl]-7-methyl-4-(2-trifluoromethyl- benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one Ic-94 2-Cyclopropyl-6-[1-(2-fluoro-6-Ib-10 Cyclopropyl boronic J 1.22 542.26methyl-phenyl)-piperidin-4-yl]-7- acid 70  (I)methyl-4-(2-trifluoromethyl-benzyl)- 72 2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one Ic-954-(2-Cyclopropyl-benzyl)-2-(2,2- Ib-12 2,2-Difluoropropyl K 1.20 552.31difluoro-propyl)-6-[1-(2-fluoro-6- 4-methyl benzene 100   (I)methyl-phenyl)-piperidin-4-yl]-7- sulfonate 72 methyl-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one Id-104-(2-Cyclopropyl-benzyl)-1-(2,2- 1.19 552.34difluoro-propyl)-6-[1-(2-fluoro-6- (I) methyl-phenyl)-piperidin-4-yl]-7-methyl-1,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one Ic-962-Cyclopropyl-4-(2-cyclopropyl- Ib-12 Cyclopropyl boronic J1 1.21 514.09benzyl)-6-[1-(2-fluoro-6-methyl- acid 70  (I)phenyl)-piperidin-4-yl]-7-methyl- 48  2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one Id-11 1-Cyclopropyl-4-(2-cyclopropyl- 1.21 514.12benzyl)-6-[1-(2-fluoro-6-methyl- (I) phenyl)-piperidin-4-yl]-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one Ic-972-Cyclopropyl-4-(2-cyclopropyl- Ib-11 Cyclopropyl boronic J1 1.11 527.40benzyl)-6-(2′-methoxy-4′-methyl- acid 100   (I) 3,4,5,6-tetrahydro-2H-5  [1,3′]bipyridinyl-4-yl)-7-methyl- 2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one Id-12 1-Cyclopropyl-4-(2-cyclopropyl- 1.13 527.40benzyl)-6-(2′-methoxy-4′-methyl- (I) 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl- 1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one Ic-98 2-Cyclopropyl-6-(2′-methoxy-4′- Ib-14Cyclopropyl boronic J1 1.15 555.37 methyl-3,4,5,6-tetrahydro-2H- acid100   (I) [1,3′]bipyridinyl-4-yl)-7-methyl-4-(2- 18 trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one Id-13 1-Cyclopropyl-6-(2′-methoxy-4′- 1.16 555.36methyl-3,4,5,6-tetrahydro-2H- (I) [1,3′]bipyridinyl-4-yl)-7-methyl-4-(2-trifluoromethyl-benzyl)-1,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one Ic-99 6-(2′-Methoxy-4′-methyl-3,4,5,6- Ib-14 Methyl 4-methyl K1.13 529.22 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- benzene sulfonate100   (I) 2,7-dimethyl-4-(2-trifluoromethyl- 1 benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one Id-146-(2′-Methoxy-4′-methyl-3,4,5,6- 1.14 529.19tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- (I)1,7-dimethyl-4-(2-trifluoromethyl- benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one Ic-100 2-(2,2-Difluoro-propyl)-5-[1-(2-Ib-13 2,2-Difluoropropyl K 1.24 580.34fluoro-6-methyl-phenyl)-piperidin-4- 4-methyl benzene 80  (I)yl]-4-methyl-7-(2-trifluoromethyl- sulfonate 18 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one Ic-1016-[1-(2-Chloro-6-fluoro-phenyl)- Ib-15 Potassium J2 1.36 562.06piperidin-4-yl]-2-cyclopropyl-7- cyclopropyl 110   (I)methyl-4-(2-trifluoromethyl-benzyl)- trifluoroborate 18 2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one Ic-1022-Cyclopropyl-6-[1-(2- Ib-16 Potassium J2 1.23 578.15difluoromethyl-6-fluoro-phenyl)- cyclopropyl 110   (I)piperidin-4-yl]-7-methyl-4-(2- trifluoroborate 18 trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one

Synthesis of Compounds of Formula if Method A (Carboxylic EsterReduction)

To a soln. of methyl ester Ic (1 eq) in anh. EtOH (12 to 22 mL/mmol) wasadded CaCl₂ (0.3 eq) and the rxn mixture was cooled to −10° C. NaBH₄(2.5 eq) was added portionwise and the mixture was stirred for 30 min at−10° C. and at a given temperature for a given time (see Table 61). Itwas quenched at 0° C. with water and EtOH was evaporated off. Theresidue was partitioned between EtOAc (or DCM respectively) and waterand the aq. phase was further extracted with EtOAc (or DCMrespectively). The combined org. phases were washed with brine, driedover MgSO₄ and concentrated in vacuo. When necessary, the crude waspurified by CC using Hept/EtOAc.

Method B (Nitrile Reduction)

To a suspension of nitrile Ic (1 eq) in anh. MeOH (28 mL/mmol) was addedCoCl₂ (1.5 eq). The rxn mixture was stirred for 5 min at RT, cooled to0° C. and NaBH₄ (5 eq) was added portionwise. The rxn mixture wasstirred for 5 min at 0° C. and at RT for a given time (see Table 61). Itwas quenched with a 10% aq. soln. of citric acid, stirred for 30 min atRT and extracted with DCM. The combined org. phases were washed withbrine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using DCM/MeOH or EtOAc/MeOH.

Method C (Saponification/Amide Coupling) Step A: Saponification

To a soln. of carboxylic ester Ic (1 eq) in THE (8 mL/mmol) was added a2M aq. soln. of NaOH (7 eq) and the rxn mixture was stirred for 1 h atRT. It was acidified with a 1M aq. soln. of HCl until pH˜3-4 andextracted with EtOAc. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo.

Step B: Amide Coupling

To a soln. of the crude carboxylic acid (1 eq) in DCM (10 to 23 mL/mmol)were sequentially added DIPEA (3 eq), HOBt (1.5 eq) and EDC·HCl (1.5eq). The rxn mixture was stirred for 5 min at RT and the appropriateamine (1.2 to 1.5 eq) pure or as soln. was added. The rxn mixture wasfurther stirred at a given temperature for a given time and partitionedbetween DCM and a sat. aq. soln. of NaHCO₃. The org. phase was washedwith water and brine, dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using Hept/EtOAc/MeOH.

Method D (Grignard Addition) Step A: Acetal Cleavage

To a soln. of acetal Ic (1 eq) in THE (7.2 mL/mmol) was added a 1M aq.soln. of HCl (2 eq) and the rxn mixture was stirred for 3 h30 at 70° C.It was quenched with a sat. aq. soln. of NaHCO₃ and extracted withEtOAc. The org. phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo.

Step B: Grignard Addition

To a soln. of the crude aldehyde (1 eq) in anh. THE (10.6 mL/mmol) wasadded dropwise at 0° C. a 3M soln. of methylmagnesium bromide in Et₂O (2eq). The rxn mixture was stirred at a given temperature for a given time(see Table 61), quenched at 0° C. with a sat. aq. soln. of NH₄Cl andextracted with EtOAc. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc/MeOH.

Method E (Reductive Amination) Step A: Acetal Cleavage

To a soln. of acetal Ic (1 eq) in THE (7.2 mL/mmol) was added a 1M aq.soln. of HCl (2 eq) and the rxn mixture was stirred for 3 h30 at 70° C.It was quenched with a sat. aq. soln. of NaHCO₃ and extracted withEtOAc. The org. phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo.

Step B: Reductive Amination

To a mixture of aldehyde Ic (1 eq) and the appropriate amine (1.2 to 2eq) (when the amine was used as HCl salt, TEA (1.2 eq) was additionallyadded) in THE (12 to 16 mL/mmol) was added AcOH (1.5 eq) and the rxnmixture was stirred for 5 min at RT. NaBH(OAc)₃ (1.5 eq) was addedportionwise and the rxn mixture was stirred at RT for a given time (seeTable 61). It was quenched with a sat. aq. soln. of NaHCO₃ and extractedwith DCM. The combined org. phases were washed with brine, dried overMgSO₄ and concentrated in vacuo. The crude was purified by CC usingDCM/MeOH or Hept/EtOAc/MeOH and/or by prep. LC-MS using method 3.

Method F (Nucleophilic Substitution)

To a soln. of Ic (1 eq) in DMF (10 mL/mmol) was added the appropriateamine (10 eq pure or as soln.). The rxn mixture was heated to a giventemperature and stirred for a given time (see Table 61). It waspartitioned between DCM and H₂O and the org. phase was washed brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc.

Method G (Dehydration of Primary Amide)

To a stirred soln. of amide intermediate Ic (1 eq) in DCM (11 mL/mmol)was added portionwise Burgess' reagent (3 eq) under argon. The rxnmixture was stirred at RT for a given time (see Table 61) andpartitioned between DCM and H₂O. The org. phase was washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc.

Method H (Boc Cleavage)

To a soln. of intermediate Ic (1 eq) in DCM (10 mL/mmol) was added TFA(2 mL/mmol) at 0° C. and the rxn mixture was stirred at RT for a giventime (see Table 61). It was cooled to 0° C., quenched with a 32% or 1Maq. soln. of NaOH until pH reached 12 to 13 and extracted with DCM. Thecombined org. phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC usingHept/EtOAc/MeOH or DCM/MeOH.

Method I (Sulfonamide Cleavage)

A soln. of intermediate Ic (1 eq) in THE (37 mL/mmol) was treated withCs₂CO₃ (3.25 eq) and QuadraPureo MPA (3 eq). The rxn mixture was heatedat 130° C. under microwave irradiation for a given time (see Table 61).It was diluted with EtOAc and filtered. The filtrate was washed with a0.5M aq. soln. of NaOH and with brine and the org. phase was dried overMgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc and/or by prep. LC-MS using method 5.

Method J (Dehydration of Tertiary Alcohol)

POCl₃ (2 eq) was added dropwise at 0° C. to a soln. of compound Ic (1eq) in pyridine (8 mL/mmol). The rxn mixture was heated to 50° C. andstirred for a given time (see Table 61). The rxn mixture was dilutedwith EtOAc and washed with a 1M aq. soln. of HCl and brine. The org.phase was dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using DCM/MeOH.

Method K (Trityl Cleavage)

Compound Ic (1 eq) was treated with TFA (9 mL/mmol) and H₂O (1 mL/mmol)at 0° C. The rxn mixture was stirred at 0° C. for a given time (seeTable 61), poured into a 1M aq. soln. of NaOH and extracted with DCM.The combined org. phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by prep. LC-MS usingmethod 9.

Method L (hydrogenation)

Compound of formula Ic (1 eq) was dissolved in EtOAc (27 mL/mmol). Theflask was evacuated three times and refilled with nitrogen. Wet Pd/C(0.05 eq) was added and the flask was evacuated three times and refilledwith hydrogen. The suspension was stirred under an atmospheric pressureof hydrogen for a given time (see Table 61) and filtered over a pad ofCelite. The cake was washed with MeOH and the filtrate was concentratedin vacuo. The crude was purified by CC using Hept/EtOAc.

TABLE 61 Method t_(R) [min] MS-data Reactant T [° C.] (LC/MS m/z If NameIc Amine time [h] method) [M + H]⁺ If-15-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-5 — A 1.01 (II) 532.26yl]-2-(2-hydroxy-ethyl)-7-(2-trifluoromethyl- 0  benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 1   d]pyrimidin-6-one (Example20) If-2 2-(2-Amino-ethyl)-5-[1-(2-fluoro-6-methyl- Ic-8 — B 0.83 (II)531.12 phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl- RTbenzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 2   d]pyrimidin-6-one (Example26) If-3 2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ic-5 25% aq. C 0.97 (II)545.15 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- soln. of 40  benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- NH₄OH 24  d]pyrimidin-2-yl]-acetamide (Example 29) If-42-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ic-5 2M soln. of C 1.02 (II) 573.24piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- dimethylamine in 40  benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- THF 5  d]pyrimidin-2-yl]-N,N-dimethyl-acetamide (Example 30) If-55-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-10 — A 1.07 (II) 560.05yl]-2-(2-hydroxy-1,1-dimethyl-ethyl)-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 3  pyrazolo[3,4-d]pyrimidin-6-one (Example 32) If-65-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 — D 1.02 (II) 546.18yl]-2-(2-hydroxy-propyl)-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 3  pyrazolo[3,4-d]pyrimidin-6-one (Example 33) If-75-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 3-Methoxyazetidine E0.85 (II) 601.11 yl]-2-[2-(3-methoxy-azetidin-1-yl)-ethyl]-7-hydrochloride RT (2-trifluoromethyl-benzyl)-2,4,5,7- 4.5tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 34) If-85-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-11 — A 1.04 (II) 560.13yl]-2-(3-hydroxy-2-methyl-propyl)-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5pyrazolo[3,4-d]pyrimidin-6-one (Example 39) If-92-(3-Amino-2-methyl-propyl)-5-[1-(2-fluoro- Ic-16 — B 0.84 (II) 559.156-methyl-phenyl)-piperidin-4-yl]-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro-  0.25pyrazolo[3,4-d]pyrimidin-6-one (Example 45) If-102-Dimethylamino-3-[5-[1-(2-fluoro-6- Ic-15 2M soln. of F 0.88 (II)617.09 methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2- dimethylamine in 70  trifluoromethyl-benzyl)-4,5,6,7-tetrahydro- THF 3  pyrazolo[3,4-d]pyrimidin-2-yl]-propionic acid methyl ester (Example 53)If-11 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 2M soln. of E0.85 (II) 545.08 yl]-2-(2-methylamino-ethyl)-7-(2- methylamine in RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- THF 18  pyrazolo[3,4-d]pyrimidin-6-one (Example 59) If-122-(2-Dimethylamino-ethyl)-5-[1-(2-fluoro-6- Ic-12 2M soln. of E 0.86(II) 559.17 methyl-phenyl)-piperidin-4-yl]-7-(2- dimethylamine in RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- THF 18  pyrazolo[3,4-d]pyrimidin-6-one (Example 60) If-135-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 Pyrrolidine E 0.88(II) 585.14 yl]-2-(2-pyrrolidin-1-yl-ethyl)-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one (Example 62) If-145-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 Piperidine E 0.90(II) 599.14 yl]-2-(2-piperidin-1-yl-ethyl)-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one (Example 63) If-155-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 Morpholine E 0.86(II) 601.14 yl]-2-(2-morpholin-4-yl-ethyl)-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one (Example 64) If-165-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 1-Methyl- E 0.84 (II)614.15 yl]-2-[2-(4-methyl-piperazin-1-yl)-ethyl]-7- piperazine RT(2-trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 65) If-172-(2-Cyclopropylamino-ethyl)-5-[1-(2- Ic-12 Cyclopropylamine E 0.86 (II)571.20 fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one (Example 71) If-185-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 N-Iso- E 0.88 (II)587.21 yl]-2-[2-(isopropyl-methyl-amino)-ethyl]-7- propylmethylamine RT(2-trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 72) If-192-[2-(Cyclopropyl-methyl-amino)-ethyl]-5- Ic-12 N-methyl- E 0.87 (II)585.20 [1-(2-fluoro-6-methyl-phenyl)-piperidin-4- cyclopropanamine RTyl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 73) If-205-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 N-(2- E 0.87 (II)603.19 yl]-2-{2-[(2-methoxy-ethyl)-methyl-amino]- Methoxyethyl) RTethyl}-7-(2-trifluoromethyl-benzyl)-2,4,5,7- methylamine 18  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 74) If-212-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ic-18 — G 1.07 (II) 541.10piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- RTbenzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 18  d]pyrimidin-2-yl]-propionitrile (Example 78) If-222-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ic-23 — G 1.09 (II) 555.07piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- RTbenzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 18  d]pyrimidin-2-yl]-2-methyl-propionitrile (Example 87) If-232-Azetidin-3-yl-5-[1-(2-fluoro-6-methyl- Ic-24 — H 0.89 (I)  543.16phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl- RTbenzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 0.4 d]pyrimidin-6-one (Example92) If-24 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-25 — H 0.86(II) 557.20 yl]-2-pyrrolidin-3-yl-7-(2-trifluoromethyl- RTbenzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 1   d]pyrimidin-6-one (Example94) If-25 2-Azetidin-2-ylmethyl-5-[1-(2-fluoro-6- Ic-26 — H 0.86 (II)557.21 methyl-phenyl)-piperidin-4-yl]-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18  pyrazolo[3,4-d]pyrimidin-6-one If-265-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-27 — H 0.87 (II) 571.21yl]-2-pyrrolidin-2-ylmethyl-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5pyrazolo[3,4-d]pyrimidin-6-one (Example 89) If-272-((R)-4,4-Difluoro-pyrrolidin-2-ylmethyl)-5- Ic-30 — H 0.94 (I)  607.19[1-(2-fluoro-6-methyl-phenyl)-piperidin-4- RTyl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7- 1.5tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 111) If-282-((S)-4,4-Difluoro-pyrrolidin-2-ylmethyl)-5- Ic-31 — H 0.94 (I)  607.16[1-(2-fluoro-6-methyl-phenyl)-piperidin-4- RTyl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7- 1.5tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 112) If-292-(2-Amino-2-methyl-propyl)-5-[1-(2-fluoro- Ic-32 — I 0.93 (I)  559.296-methyl-phenyl)-piperidin-4-yl]-7-(2- 130   trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 0.5pyrazolo[3,4-d]pyrimidin-6-one (Example 118) If-30(S)-2-(Azetidin-2-ylmethyl)-5-[1-(2-fluoro-6- Ic-33 — H 0.91 (I)  557.19methyl-phenyl)-piperidin-4-yl]-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 5  pyrazolo[3,4-d]pyrimidin-6-one (Example 122) If-31(R)-2-(Azetidin-2-ylmethyl)-5-[1-(2-fluoro-6- Ic-34 — H 0.91 (I)  557.14methyl-phenyl)-piperidin-4-yl]-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 4  pyrazolo[3,4-d]pyrimidin-6-one (Example 130) If-325-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-9 — J 1.32 (I)  542.18yl]-2-(2-methyl-propenyl)-7-(2- 50  trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 0.5pyrazolo[3,4-d]pyrimidin-6-one (Example 153) If-335-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- 1.28 (I)  542.17yl]-2-(2-methyl-allyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 154)If-34 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-42 — K 1.11 (I) 557.13 yl]-2-(2-oxo-azetidin-3-yl)-7-(2- 0  trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 72  pyrazolo[3,4-d]pyrimidin-6-one (Example 157) If-356-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-74 — L 1.22 (I)  530.05yl]-2-isopropyl-4-(2-trifluoromethyl-benzyl)- RT2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 18   5-one (Example 191)

Synthesis of Compounds of Formula Ig Method A (Carboxylic EsterReduction)

To a soln. of methyl ester If (1 eq) in anh. EtOH (23 mL/mmol) was addedCaCl₂ (0.3 eq) and the rxn mixture was cooled to −10° C. NaBH₄ (4 eq)was added portionwise and the mixture was stirred for 15 min at −10° C.and at a given temperature for a given time (see Table). When necessaryto reach completion of the rxn, a further amount of NaBH₄ (4 eq) wasadded. It was quenched at 0° C. with water and EtOH was evaporated off.The residue was partitioned between DCM and water and the aq. phase wasfurther extracted with DCM. The combined org. phases were washed withbrine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc.

Method B(Acylation/Alkoxycarbonylation/Dialkylcarbamylation/Alkylsulfonylation/Dialkylsulfamylation)

A soln. of amine If (1 eq) and TEA (1.5 to 6 eq) in DCM (0.5 to 36mL/mmol) (or DMF, respectively) was cooled to 0° C. and halide BB-25(1.1 to 2 eq) (or pentafluorophenylcarbonate BB-25, respectively) wasadded dropwise at 0° C. (or at RT, respectively). The rxn mixture wasallowed to slowly reach RT and stirred for a given time (or stirred at agiven temperature for a given time, respectively) (see Table). It wasdiluted with DCM and washed with a 10% aq. soln. of citric acid whensuitable, with a sat. aq. soln. of NaHCO₃ and with brine. The org. phasewas dried over MgSO₄ and concentrated in vacuo. The crude was purifiedby CC using Hept/EtOAc or DCM/MeOH and/or by prep. LC-MS using methods 3or 8.

Method C (Boc Protection)

To a soln. of amine If (1 eq) in anh. THE (2 mL/mmol) was added TEA (3eq). The rxn mixture was cooled to 0° C. and Boc₂O (1.5 eq) was added.It was stirred for 5 min at 0° C. and at RT for a given time (see Table)and was partitioned between DCM and water. The org. phase was washedwith brine, dried over MgSO₄ and concentrated in vacuo. When necessary,the crude was purified by CC using Hept/EtOAc.

Method D (Nitrile Reduction)

Nitrile If (1 eq) was suspended in a 7M soln. of NH₃ in MeOH (40mL/mmol). The flask was evacuated and refilled with nitrogen. Raneynickel (0.1 eq) was added at 0° C. and the temperature was allowed toreach RT. The flask was evacuated and refilled with hydrogen. Thesuspension was stirred under a hydrogen atmosphere at RT for a giventime (see Table) and filtered over a pad of Celite. The cake was washedwith MeOH and the filtrate was concentrated in vacuo.

Method E Step A: Mitsunobu

To a suspension of alcohol If (1 eq) and phtalimide (1.5 eq) in toluene(16 mL/mmol) was added a 1M soln. of(tributylphosphoranylidene)acetonitrile in toluene (2 eq) under argon.The rxn mixture was heated to 110° C. and stirred for 18 h. It wasquenched with water and extracted with DCM. The combined org. phaseswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using Hept/EtOAc and/or DCM/MeOH.

Step B: Phtalimide Cleavage

A soln. of the crude from previous step (1 eq) was dissolved in EtOH (35mL/mmol) and treated with hydrazine hydrate (20 eq). The rxn mixture washeated to 80° C. and stirred for a given time (see Table). It wasbasified with a 1M aq. soln. of NaOH and partitioned between DCM andH₂O. The org. phase was dried over MgSO₄ and concentrated in vacuo. Thecrude was purified by CC using DCM/MeOH.

Method F (Reductive Amination)

To a stirred soln. of amine If (1 eq) in a mixture of DCM (10 mL/mmol)and MeOH (15 mL/mmol) or in THE (7 to 8.5 mL/mmol) was addedsuccessively AcOH (1.2 to 1.5 eq), the appropriate aldehyde BB-25 (1.3to 2 eq) and NaBH(OAc)₃ (1.5 to 2 eq). The rxn mixture was stirred at RTfor a given time (see Table) and the volatiles were evaporated in vacuo.The residue was partitioned between DCM and a sat. aq. soln. of NaHCO₃.The org. phase was dried over MgSO₄ and concentrated in vacuo. The crudewas purified by CC using Hept/EtOAc.

Method G (Alkylation)

To a soln. of amine If (1 eq) in DMF (10 mL/mmol) was added theappropriate halide BB-25 (3 eq), DIPEA (2 eq) and KI (0.05 eq). The rxnmixture was heated at 150° C. under microwave irradiation for a giventime (see Table) and partitioned between EtOAc and H₂O. The org. phasewas washed with H₂O and brine, dried over MgSO₄ and concentrated invacuo. The crude was purified by CC using Hept/EtOAc.

Method H (Urea Formation)

A soln. of amine If (1 eq) and TEA (4 eq) in THE (12 mL/mmol) wastreated with CDI (1.5 eq) and the rxn mixture was stirred at RT for 15min. Amine BB-25 (1.5 eq) was added at RT and the mixture was stirred ata given temperature for a given time (see Table). When necessary toreach completion of the rxn, extra amounts of amine (1 to 10 eq) wereadded. The rxn mixture was partitioned between DCM and H₂O and the org.phase was washed with brine, dried over MgSO₄ and concentrated in vacuo.The crude was purified by CC using DCM/MeOH and/or by prep. LC-MS usingmethod 4.

Method I (PyBOP Activated SNAr)

Compound If (1 eq), heteroarene BB-25 (1.5 eq) and DIPEA (2 eq) weredissolved in anh. DMF (5 mL/mmol) and the mixture was stirred for 5 minat RT. PyBOP (1.6 eq) was added portionwise and the rxn mixture wasfurther stirred at RT for a given time (see Table). It was partitionedbetween EtOAc and a 5% aq. soln. of KHSO₄ and the org. phase was washedwith a sat. aq. soln. of NaHCO₃ and brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

Method J (SNAr)

To a soln. of compound If (1 eq) in DMSO (5 mL/mmol) was added DIPEA (3eq) and halo-heteroarene BB-25 (1.2 eq). The rxn mixture was stirred atRT for a given time (see Table) and partitioned between EtOAc and a 5%aq. soln. of KHSO₄. The org. phase was washed with a 5% aq. soln. ofKHSO₄ and brine, dried over MgSO₄ and concentrated in vacuo. The crudewas purified by CC using Hept/EtOAc.

Method K (Hydrogenation)

Compound of formula If (1 eq) was dissolved in EtOH (10 mL/mmol). Theflask was evacuated three times and refilled with nitrogen. Wet Pd/C(0.02 eq) was added and the flask was evacuated three times and refilledwith hydrogen. The suspension was stirred under an atmospheric pressureof hydrogen for a given time (see Table) and filtered over a pad ofCelite. The cake was washed with MeOH and the filtrate was concentratedin vacuo.

TABLE 62 Method t_(R) [min] MS-data Reactant Reactant T [° C.] (LC/MSm/z Ig Name If BB-25 time [h] method) [M + H]⁺ Ig-12-(2-Dimethylamino-3-hydroxy-propyl)-5- If-10 — A  0.85 (II) 589.12[1-(2-fluoro-6-methyl-phenyl)-piperidin-4- RTyl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 56) Ig-2N-{2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-2 Acetyl B  1.02 (II) 573.15piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloride RTbenzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 2  d]pyrimidin-2-yl]-ethyl]-acetamide (Example 66) Ig-3{2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-2 — C  1.09 (II) 631.15piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- RTbenzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 18  d]pyrimidin-2-yl]-ethyl}-carbamic acid tert- butyl ester (Example 67)Ig-4 2-(2-Amino-1-methyl-ethyl)-5-[1-(2-fluoro- If-21 — D  0.86 (II)545.23 6-methyl-phenyl)-piperidin-4-yl]-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 2  pyrazolo[3,4-d]pyrimidin-6-one (Example 79) Ig-52-(2-Amino-propyl)-5-[1-(2-fluoro-6- If-6 — E  0.81 (II) 545.13methyl-phenyl)-piperidin-4-yl]-7-(2- 80  trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 2  pyrazolo[3,4-d]pyrimidin-6-one (Example 80) Ig-62-(2-Amino-1,1-dimethyl-ethyl)-5-[1-(2- If-22 — D  0.88 (II) 559.25fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- RT(2-trifluoromethyl-benzyl)-2,4,5,7- 3.5tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 88) Ig-75-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 Formaldehyde F 0.91 (I)557.16 4-yl]-2-(1-methyl-azetidin-3-yl)-7-(2- (as a 37% soln. RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- in H₂O) 1.5pyrazolo[3,4-d]pyrimidin-6-one (Example 102) Ig-82-(1-Ethyl-azetidin-3-yl)-5-[1-(2-fluoro-6- If-23 Acetaldehyde F 0.93(I) 571.19 methyl-phenyl)-piperidin-4-yl]-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5pyrazolo[3,4-d]pyrimidin-6-one (Example 103) Ig-95-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 Isobutyraldehyde F 0.98(I) 599.23 4-yl]-2-(1-isobutyl-azetidin-3-yl)-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5pyrazolo[3,4-d]pyrimidin-6-one (Example 104) Ig-105-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 Acetone F 0.95 (I)585.18 4-yl]-2-(1-isopropyl-azetidin-3-yl)-7-(2- RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 0.5pyrazolo[3,4-d]pyrimidin-6-one (Example 105) Ig-112-[1-(2,2-Difluoro-ethyl)-azetidin-3-yl]-5- If-23 2-Bromo-1,1- G 0.95(I) 607.18 [1-(2-fluoro-6-methyl-phenyl)-piperidin-4- difluoroethane150    yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7-  0.25tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 106) Ig-122-[1-(2-Fluoro-ethyl)-azetidin-3-yl]-5-[1- If-23 1-Chloro-2- G 0.93 (I)589.20 (2-fluoro-6-methyl-phenyl)-piperidin-4-yl]- fluoroethane 150   7-(2-trifluoromethyl-benzyl)-2,4,5,7-  0.25tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 107) Ig-132-(1-Acetyl-pyrrolidin-3-yl)-5-[1-(2-fluoro- If-24 Acetyl B 1.24 (I)599.21 6-methyl-phenyl)-piperidin-4-yl]-7-(2- chloride RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 0.5pyrazolo[3,4-d]pyrimidin-6-one (Example 113) Ig-142-(1-Acetyl-azetidin-2-ylmethyl)-5-[1-(2- If-25 Acetyl B 1.20 (I) 599.26fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- chloride RT(2-trifluoromethyl-benzyl)-2,4,5,7- 0.5tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 114) Ig-152-(1-Acetyl-pyrrolidin-2-ylmethyl)-5-[1-(2- If-26 Acetyl B 1.21 (I)613.25 fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- chloride RT(2-trifluoromethyl-benzyl)-2,4,5,7- 0.5tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 115) Ig-162-(1-Acetyl-azetidin-3-yl)-5-[1-(2-fluoro-6- If-23 Acetyl B 1.22 (I)585.21 methyl-phenyl)-piperidin-4-yl]-7-(2- chloride RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1  pyrazolo[3,4-d]pyrimidin-6-one (Example 116) Ig-173-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Methyl B 1.21 (I) 601.18piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RTbenzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 1  d]pyrimidin-2-yl]-azetidine-1-carboxylic acid methyl ester (Example 117)Ig-18 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Dimethylamine H 1.24 (I)614.25 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- (as 2M soln. in 45  benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- THF) 18  d]pyrimidin-2-yl]-azetidine-1-carboxylic acid dimethylamide (Example119) Ig-19 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Methylamine H 1.17(I) 600.19 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- (as 2M soln. in45   benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- THF) 18  d]pyrimidin-2-yl]-azetidine-1-carboxylic acid methylamide (Example 120)Ig-20 (S)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-30 Methyl B 1.21 (I)615.16 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RTbenzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-  0.25d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid methyl ester(Example 123) Ig-21 (S)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-30 EthylB 1.23 (I) 629.18 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-  0.25d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid ethyl ester(Example 124) Ig-22 (S)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-30Isopropyl B 1.26 (I) 643.11 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4-  0.25d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid isopropyl ester(Example 125) Ig-23 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Ethyl B1.25 (I) 615.21 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 2  d]pyrimidin-2-yl]-azetidine-1-carboxylic acid ethyl ester (Example 126)Ig-24 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Isopropyl B 1.27 (I)629.21 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RTbenzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 2  d]pyrimidin-2-yl]-azetidine-1-carboxylic acid isopropyl ester (Example127) Ig-25 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 Isobutyryl B1.24 (I) 613.29 4-yl]-2-(1-isobutyryl-azetidin-3-yl)-7-(2- chloride RTtrifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5pyrazolo[3,4-d]pyrimidin-6-one (Example 131) Ig-263-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Isobutyl B 1.29 (I) 643.23piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RTbenzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 1.5d]pyrimidin-2-yl]-azetidine-1-carboxylic acid isobutyl ester (Example132) Ig-27 (R)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-31 Methyl B 1.22(I) 615.15 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RTbenzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 0.5d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid methyl ester(Example 133) Ig-28 (R)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-31 EthylB 1.24 (I) 629.16 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 0.5d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid ethyl ester(Example 134) Ig-29 (R)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-31Isopropyl B 1.26 (I) 643.11 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl-chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 0.5d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid isopropyl ester(Example 135) Ig-30 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23Methanesulfonyl B 1.20 (I) 621.214-yl]-2-(1-methanesulfonyl-azetidin-3-yl)- chloride RT7-(2-trifluoromethyl-benzyl)-2,4,5,7- 3  tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 136) Ig-313-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 N,N- B 1.23 (I) 650.14piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- Dimethylsulfamoyl RTbenzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- chloride 3  d]pyrimidin-2-yl]-azetidine-1-sulfonic acid dimethylamide (Example 137)Ig-32 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 BB-25-1 B 1.19 (I)643.12 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- 110   benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 1  d]pyrimidin-2-yl]-azetidine-1-carboxylic acid oxetan-3-yl ester (Example139) Ig-33 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 BB-25-2 B 1.27 (I)711.15 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- 110   benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 1  d]pyrimidin-2-yl]-azetidine-1-carboxylic acid3-trifluoromethyl-oxetan-3-yl ester (Example 140) Ig-343-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 BB-25-3 B 1.24 (I) 657.11piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- 110   benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 1  d]pyrimidin-2-yl]-azetidine-1-carboxylic acid 3-methyl-oxetan-3-yl ester(Example 141) Ig-35 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-235-Methyl-3H- I 1.24 (I) 625.044-yl]-2-[1-(5-methyl-[1,3,4]oxadiazol-2-yl)- [1,3,4]oxadiazol- RTazetidin-3-yl]-7-(2-trifluoromethyl-benzyl)- 2-one 1.52,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 142) Ig-365-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 BB-25-4 I 1.28 (I)653.15 4-yl]-2-[1-(5-isopropyl-[1,3,4]oxadiazol-2- RTyl)-azetidin-3-yl]-7-(2-trifluoromethyl- 1.5benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 143)Ig-37 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 2-Iodo-5- J 1.26(I) 679.11 4-yl]-7-(2-trifluoromethyl-benzyl)-2-[1-(5-(trifluoromethyl)- RT trifluoromethyl-[1,3,4]oxadiazol-2-yl)-1,3,4-oxadiazole 1   azetidin-3-yl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 144) Ig-385-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-33 — K 1.28 (I) 544.114-yl]-2-isobutyl-7-(2-trifluoromethyl- RTbenzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 5   d]pyrimidin-6-one (Example155)

Synthesis of Compounds of Formula Ih Method A (Deuteration)

Compound of formula Ia (1 eq) was dissolved in a mixture of CD₃OD (12mL/mmol) and EtOAc (4 mL/mmol). The flask was evacuated three times andrefilled with nitrogen. Wet Pd/C (0.1 eq) was added and the flask wasevacuated three times and refilled with deuterium. The suspension wasstirred under an atmospheric pressure of deuterium for a given time (seeTable) and filtered over a pad of Celite. The cake was washed with EtOAcand the filtrate was concentrated in vacuo. The crude was purified byprep. LC-MS using method 4.

Method B (Substitution with F)

A suspension of compound Ia (1 eq) and dry CsF (6 eq) in anh. DMSO (5.4mL/mmol) was heated to a given temperature under argon and stirred for agiven time (see Table). The rxn mixture was partitioned between EtOAcand H₂O and the org. phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

Method C (Suzuki Coupling)

A mixture of compound Ia (1 eq), boron species (1.1 eq),Pd(dppf)Cl₂·CH₂Cl₂ (0.03 eq) and K₂CO₃ (2 eq) in dioxane (13.6 mL/mmol)was flushed with N₂ and heated at a given temperature for a given time(see Table). It was partitioned between EtOAc and a sat. aq. soln. ofNaHCO₃ and the org. phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC usingHept/EtOAc/MeOH.

Method D (Substitution with OMe)

A suspension of compound Ia (1 eq) in MeOH (6 mL) was treated with a 25%soln. of NaOMe in MeOH (6 eq). The rxn mixture was heated to a giventemperature for a given time (see Table) and partitioned between DCM andwater. The org. phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

Method E (Substitution with Amine)

A soln. of compound Ia (1 eq) in MeOH (9 mL/mmol) was treated with theappropriate amine (21 eq, pure or as soln.). The rxn mixture was heatedat 150° C. under microwave irradiation for a given time (see Table) andpartitioned between DCM and H₂O. The org. phase was washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc.

Method F (Phenol Alkylation Using NaH as Base)

To a soln. of compound Ia (1 eq) in anh. THE (9.7 mL/mmol) was added NaH(5 eq, as a 60% dispersion in mineral oil) at 0° C. The suspension wasstirred for 10 min and the appropriate halide (1.1 to 1.5 eq) was addedat 0° C. The rxn mixture was stirred at a given temperature for a giventime (see Table). When necessary to reach completion of the rxn, extraamounts of NaH (5 eq, as a 60% dispersion in mineral oil) and/or halideBB-9 (3 eq) were added. The mixture was quenched with water at 0° C. andextracted with EtOAc. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc or by prep. LC-MS using method 11.

Method G (Phenol Alkylation Using K₂CO₃ as Base)

To a stirred suspension of compound Ia (1 eq) in DMF (8.5 mL/mmol) wasadded K₂CO₃ (3 eq) followed by the appropriate halide (5 eq). The rxnmixture was stirred at a given temperature under microwave irradiationfor a given time (see Table). It was partitioned between EtOAc and H₂Oand the org. phase was washed with water and brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

Method H (Phenol Alkylation Using Mitsunobu Conditions)

To a soln. of compound Ia (1 eq) and alcohol (3 eq) in toluene (8mL/mmol) was added a 1M soln. of (tributylphosphoranylidene)acetonitrilein toluene (1.5 eq) under argon. The rxn mixture was heated to 110° C.and stirred for a given time (see Table). It was quenched with water andextracted with D M. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc and/or by prep. LC-MS using method 11.

TABLE 63 Amine/ halide/ alcohol/ Method t_(R) [min] MS-data Reactantboron T [° C.] (LC/MS m/z Ih Name Ia reagent time [h] method) [M + H]⁺Ih-1 5-(1-(2-fluoro-6- Ia-9 — A 1.00 (II) 504.12methylphenyl)piperidin-4-yl)-2- RT methyl-7-(3-trifluoromethyl-[6-   48²H]pyridine-2-yl-methyl)-2,4,5,7- tetrahydro-6H-pyrazolo[3,4-d]pyrimidin-6-one (Example 23) Ih-2 5-[1-(2-Fluoro-6-methyl-phenyl)-Ia-9 — B 1.03 521.11 piperidin-4-yl]-7-(6-fluoro-3-  100trifluoromethyl-pyridin-2-ylmethyl)-2-   3 methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 36) Ih-35-[1-(2-Fluoro-6-methyl-phenyl)- Ia-9 Trimethyl C 1.03 (I)  517.13piperidin-4-yl]-2-methyl-7-(6-methyl- boroxine  1003-trifluoromethyl-pyridin-2-ylmethyl)-   22,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 37) Ih-45-[1-(2-Fluoro-6-methyl-phenyl)- Ia-9 25% soln. of D 1.05 (II) 533.13piperidin-4-yl]-7-(6-methoxy-3- NaOMe in MeOH   70trifluoromethyl-pyridin-2-ylmethyl)-2-   2 methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 38) Ih-5 7-(6-Dimethylamino-3-Ia-9 2M soln. of E 1.05 (II) 546.06trifluoromethyl-pyridin-2-ylmethyl)-5- dimethylamine in  150[1-(2-fluoro-6-methyl-phenyl)- THF   1 piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 50) Ih-65-[1-(2-Fluoro-6-methyl-phenyl)- Ia-9 2M soln. of E 0.99 (II) 532.13piperidin-4-yl]-2-methyl-7-(6- methylamine in  150methylamino-3-trifluoromethyl- THF   4 pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 51) Ih-77-(2-Cyclopropylmethoxy-benzyl)-5- Ia-39 (Bromomethyl) F 1.20 (I) 504.25 [1-(2-fluoro-6-methyl-phenyl)- cyclopropane RTpiperidin-4-yl]-2-methyl-2,4,5,7- totetrahydro-pyrazolo[3,4-d]pyrimidin- 70120 6-one (Example 248) Ih-85-[1-(2-Fluoro-6-methyl-phenyl)- Ia-39 3-Bromooxetane G 1.10 (I)  506.20piperidin-4-yl]-2-methyl-7-[2-(oxetan-  1503-yloxy)-benzyl]-2,4,5,7-tetrahydro-   7 pyrazolo[3,4-d]pyrimidin-6-one(Example 250) Ih-9 5-[1-(2-Fluoro-6-methyl-phenyl)- Ia-39 2-Propanol H1.19 (I)  492.20 piperidin-4-yl]-7-(2-isopropoxy-  110benzyl)-2-methyl-2,4,5,7-tetrahydro-   18 pyrazolo[3,4-d]pyrimidin-6-one(Example 251)

Synthesis of Compounds of Formula II Method A (Alkylation Using NaH)

To a suspension or soln. of intermediate C-2 (1 eq) in a mixture of anh.THE (3 to 3.6 mL/mmol) and anh. DMF (0.1 to 0.25 mL/mmol) was added NaH(2 eq, as a 60% dispersion in mineral oil) at 0° C. The suspension wasstirred for 10 min at 0° C. and BB-9 (1.2 to 1.5 eq) was added at 0° C.The rxn mixture was stirred at a given temperature for a given time (seeTable), quenched at 0° C. with a sat. aq. soln. of NaHCO₃ and extractedwith EtOAc or DCM. The combined org. phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc.

Method B (Mitsunobu)

To a soln. or suspension of intermediate C-2 (1 eq) and alcohol BB-9(1.1 to 1.3 eq) in toluene (7 mL/mmol) was added a 1M soln. of(tributylphosphoranylidene)acetonitrile in toluene (2 eq) under argon.The rxn mixture was heated to a given temperature and stirred for agiven time (see Table). When necessary to reach completion of the rxn,extra amounts of a 1M soln. of (tributylphosphoranylidene)acetonitrilein toluene (0.2 eq) were sequentially added under argon. It was quenchedwith water or a sat. aq. soln. of NaHO₃ and extracted with EtOAc or DCM.The combined org. phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude was purified by CC using Hept/EtOAc orDM/MeOH. When necessary, an additional purification by prep. L-MS usingmethods 2, 3, 4 or 5 was performed.

TABLE 64 Method t_(R) [min] MS-data Reactant Reactant T [° C.] (LC/MS-m/z Ii Name C-2 BB-9 time [h] method) [M + H]⁺ Ii-13-[2-Methyl-6-oxo-7-(2-trifluoromethyl- C-2-1 BB-9-1 A 0.94 (II) 480.08benzyl)-2,4,6,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-5-yl]- 18  pyrrolidine-1-carboxylic acid tert-butyl ester Ii-24-[2-Methyl-6-oxo-7-(2-trifluoromethyl- C-2-2 BB-9-1 A 0.97 (II) 494.09benzyl)-2,4,6,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-5-yl]- 18  piperidine-1-carboxylic acid tert-butyl ester Ii-34-[2-Methyl-6-oxo-7-(2-trifluoromethyl- C-2-3 BB-9-1 A 0.98 (II) 508.19benzyl)-2,4,6,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-5-yl]- 18  azepane-1-carboxylic acid tert-butyl ester Ii-44-[2-Methyl-5-oxo-4-(2-trifluoromethyl- C-2-4 BB-9-1 A 1.07 (I)  494.21benzyl)-2,4,5,7-tetrahydro- RT pyrazolo[4,3-d]pyrimidin-6-yl]- 2  piperidine-1-carboxylic acid tert-butyl ester Ii-54-{2-Methyl-6-oxo-7-[1-(2- C-2-2 BB-9-15 B 1.07 (I)  508.26trifluoromethyl-phenyl)-ethyl]-2,4,6,7- 110   tetrahydro-pyrazolo[3,4-d]pyrimidin-5- 24   yl}-piperidine-1-carboxylicacid tert- butyl ester Ii-6 4-[7-(2-Cyclopropyl-benzyl)-2-methyl- C-2-2BB-9-9 B 1.05 (I)  466.03 6-oxo-2,4,6,7-tetrahydro-pyrazolo[3,4- 110   d]pyrimidin-5-yl]-piperidine-1- 1.5 carboxylic acid tert-butyl ester

Synthesis of Compounds of Formula Ij Method A (Buchwald Coupling)

To a mixture of intermediate C-3 (1 eq), halo-(hetero)arene BB-16 (1.1to 2 eq) and sodium tert-butoxide (2 to 2.3 eq) in toluene (3 to 7.8mL/mmol) under N₂, was added BINAP (0.2 to 0.3 eq) and Pd₂(dba)₃ (0.1 to0.15 eq). The rxn mixture was flushed with N₂, heated under stirring ata given temperature for a given time (see Table). It was partitionedbetween water and EtOAc or DCM and the org. phase was washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude was purified by CCusing Hept/EtOAc or DCM/MeOH. When necessary, an additional purificationby prep. LC-MS using methods 1, 3, 4, 5, 6 or 10 was performed.

Method B (Aromatic Nucleophilic Substitution)

To a soln. of intermediate C-3 (1 eq) and halo-(hetero)arene BB-16 (1.2to 2 eq) in DMSO (1.5 to 4.5 mL/mmol) was added K₂CO₃ or CsF (2 eq) andthe mixture was heated to a given temperature and stirred for a giventime under possible microwave irradiation (see Table). It waspartitioned between EtOAc and H₂O. The org. phase was washed with H₂Oand brine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc.

When necessary, an additional purification by prep. LC-MS using method 1was performed.

TABLE 58 Method t_(R) [min] MS-data Reactant Reactant T [° C.] (LC/MS-m/z Ij Name C-3 BB-16 time [h] method) [M + H]⁺ Ij-15-[1-(2-Fluoro-6-methyl-phenyl)- C-3-1 BB-16-1 A  0.92 (II) 488.06pyrrolidin-3-yl]-2-methyl-7-(2- 110    trifluoromethyl-benzyl)-2,4,5,7-2.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 44) Ij-25-[1-(2,6-Dimethyl-phenyl)-piperidin- C-3-2 BB-16-2 A  1.08 (II) 498.014-yl]-2-methyl-7-(2-trifluoromethyl- 110    benzyl)-2,4,5,7-tetrahydro-18   pyrazolo[3,4-d]pyrimidin-6-one (Example 47) Ij-35-[1-(2-Methoxy-6-methyl-phenyl)- C-3-2 BB-16-3 A  0.91 (II) 514.01piperidin-4-yl]-2-methyl-7-(2- 110    trifluoromethyl-benzyl)-2,4,5,7-18   tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 48) Ij-43-Fluoro-2-{4-[2-methyl-6-oxo-7-(2- C-3-2 BB-16-5 B  1.02 (II) 513.00trifluoromethyl-benzyl)-2,4,6,7- 100   tetrahydro-pyrazolo[3,4-d]pyrimidin- 3.55-yl]-piperidin-1-yl}-benzonitrile (Example 49) Ij-55-[1-(2,6-Dimethyl-phenyl)- C-3-1 BB-16-2 A  0.95 (II) 484.10pyrrolidin-3-yl]-2-methyl-7-(2- 110    trifluoromethyl-benzyl)-2,4,5,7-18   tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one Ij-65-(2′-Fluoro-4′-methyl-3,4,5,6- C-3-2 BB-16-6 A  1.01 (II) 503.10tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 110   2-methyl-7-(2-trifluoromethyl- 18   benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 52) Ij-75-(2′-Methoxy-4′-methyl-3,4,5,6- C-3-2 BB-16-7 A  1.01 (II) 515.11tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 110   2-methyl-7-(2-trifluoromethyl- 18   benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 54) Ij-85-(3′-Fluoro-3,4,5,6-tetrahydro-2H- C-3-2 BB-16-8 A  0.90 (II) 489.12[1,2′]bipyridinyl-4-yl)-2-methyl-7-(2- 110   trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 68) Ij-92-Methyl-5-(3′-methyl-3,4,5,6- C-3-2 BB-16-9 A  0.73 (II) 485.12tetrahydro-2H-[1,2′]bipyridinyl-4-yl)- 110   7-(2-trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 69) Ij-105-(3′-Methoxy-3,4,5,6-tetrahydro-2H- C-3-2 BB-16-10 A  0.74 (II) 501.11[1,2′]bipyridinyl-4-yl)-2-methyl-7-(2- 110   trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 70) Ij-114′-Methyl-4-[2-methyl-6-oxo-7-(2- C-3-2 BB-16-11 A  0.98 (II) 510.11trifluoromethyl-benzyl)-2,4,6,7- 110   tetrahydro-pyrazolo[3,4-d]pyrimidin- 18   5-yl]-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-carbonitrile (Example 85) Ij-125-(4′-Fluoro-2′-methyl-3,4,5,6- C-3-2 BB-16-12 A  0.74 (II) 503.10tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 110   2-methyl-7-(2-trifluoromethyl- 18   benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 86) Ij-135-(2′,4′-Dimethoxy-3,4,5,6- C-3-2 BB-16-13 A  0.76 (II) 531.09tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 110   2-methyl-7-(2-trifluoromethyl- 18   benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 95) Ij-145-[1-(4-Methoxy-6-methyl-pyrimidin- C-3-2 BB-16-14 A  0.84 (II) 516.115-yl)-piperidin-4-yl]-2-methyl-7-(2- 110   trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 96) Ij-155-[1-(4,6-Dimethoxy-pyrimidin-5-yl)- C-3-2 BB-16-15 A  0.93 (II) 532.09piperidin-4-yl]-2-methyl-7-(2- 110    trifluoromethyl-benzyl)-2,4,5,7-18   tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 100) Ij-161,3-Dimethyl-5-{4-[2-methyl-6-oxo-7- C-3-2 BB-16-16 B 1.04 (I) 513.01(2-trifluoromethyl-benzyl)-2,4,6,7- 130   tetrahydro-pyrazolo[3,4-d]pyrimidin- 2.55-yl]-piperidin-1-yl}-1H-pyrazole-4- microwave carbonitrile (Example229) Ij-18 5-[1-(2-Fluoro-6-trifluoromethyl- C-3-2 BB-16-19 A 1.22 (I)556.19 phenyl)-piperidin-4-yl]-2-methyl-7-(2- 110   trifluoromethyl-benzyl)-2,4,5,7- 2.5tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 243) Ij-195-[1-(2-Fluoro-6-trifluoromethoxy- C-3-2 BB-16-20 A 1.22 (I) 572.17phenyl)-piperidin-4-yl]-2-methyl-7-(2- 110   trifluoromethyl-benzyl)-2,4,5,7- 2.5tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 244) Ij-205-[1-(2-Chloro-6-methyl-phenyl)- C-3-2 BB-16-21 A 1.22 (I) 518.17piperidin-4-yl]-2-methyl-7-(2- 110    trifluoromethyl-benzyl)-2,4,5,7-2.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 245) Ij-215-[1-(2-Isopropyl-phenyl)-piperidin-4- C-3-2 BB-16-22 A 1.06 (I) 512.24yl]-2-methyl-7-(2-trifluoromethyl- 110    benzyl)-2,4,5,7-tetrahydro-2   pyrazolo[3,4-d]pyrimidin-6-one (Example 257) Ij-225-[1-(2-Cyclopropyl-phenyl)- C-3-2 BB-16-23 A 1.02 (I) 510.24piperidin-4-yl]-2-methyl-7-(2- 110    trifluoromethyl-benzyl)-2,4,5,7-2   tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 258) Ij-236-[1-(2-Fluoro-6-trifluoromethoxy- C-3-4 BB-16-20 A 1.25 (I) 572.23phenyl)-piperidin-4-yl]-2-methyl-4-(2- 110   trifluoromethyl-benzyl)-2,4,6,7- 18  tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 270) Ij-246-[1-(2-Fluoro-6-trifluoromethyl- C-3-4 BB-16-19 A 1.24 (I) 556.23phenyl)-piperidin-4-yl]-2-methyl-4-(2- 100   trifluoromethyl-benzyl)-2,4,6,7- 18  tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 271) Ij-255-[1-(2-Chloro-6-fluoro-phenyl)- C-3-2 BB-16-24 A 1.19 (I) 522.18piperidin-4-yl]-2-methyl-7-(2- 100    trifluoromethyl-benzyl)-2,4,5,7-2.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 272) Ij-265-[1-(2,6-Difluoro-phenyl)-piperidin- C-3-2 BB-16-25 A 1.15 (I) 506.184-yl]-2-methyl-7-(2-trifluoromethyl- 100    benzyl)-2,4,5,7-tetrahydro-2.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 273) Ij-275-(2′-Methoxy-4′-methyl-3,4,5,6- C-3-5 BB-16-7 A 1.11 (I) 529.16tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 100   2-methyl-7-[1-(2-trifluoromethyl- 2   phenyl)-ethyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ij-28 3-Fluoro-2-(4-{2-methyl-6-oxo-7-[1-C-3-5 BB-16-5 B 1.13 (I) 527.27 (2-trifluoromethyl-phenyl)-ethyl]-100    2,4,6,7-tetrahydro-pyrazolo[3,4- 5  d]pyrimidin-5-yl}-piperidin-1-yl)- benzonitrile Ij-295-[1-(2,6-Difluoro-phenyl)-piperidin- C-3-5 BB-16-25 A 1.16 (I) 520.274-yl]-2-methyl-7-[1-(2-trifluoromethyl- 100   phenyl)-ethyl]-2,4,5,7-tetrahydro- 2   pyrazolo[3,4-d]pyrimidin-6-oneIj-30 7-(2-Cyclopropyl-benzyl)-5-[1-(2- C-3-6 BB-16-19 A 1.22 (I) 528.31fluoro-6-trifluoromethyl-phenyl)- 100   piperidin-4-yl]-2-methyl-2,4,5,7- 4  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 280) Ij-317-(2-Cyclopropyl-benzyl)-5-[1-(2- C-3-6 BB-16-20 A 1.22 (I) 544.31fluoro-6-trifluoromethoxy-phenyl)- 100   piperidin-4-yl]-2-methyl-2,4,5,7- 1.5tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 281) Ij-322-{4-[7-(2-Cydopropyl-benzyl)-2- C-3-6 BB-16-5 B 1.13 (I) 485.25methyl-6-oxo-2,4,6,7-tetrahydro- 100    pyrazolo[3,4-d]pyrimidin-5-yl]-4   piperidin-1-yl}-3-fluoro-benzonitrile (Example 282) Ij-337-(2-Cyclopropyl-benzyl)-5-(2′- C-3-6 BB-16-7 A 1.10 (I) 487.28methoxy-4′-methyl-3,4,5,6- 100    tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2   2-methyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example283) Ij-34 5-[1-(2-Chloro-6-fluoro-phenyl)- C-3-6 BB-16-24 A 1.19 (I)494.27 piperidin-4-yl]-7-(2-cyclopropyl- 100   benzyl)-2-methyl-2,4,5,7-tetrahydro- 2   pyrazolo[3,4-d]pyrimidin-6-one(Example 284) Ij-35 7-(2-Cyclopropyl-benzyl)-5-[1-(2,6- C-3-6 BB-16-25 A1.14 (I) 478.31 difluoro-phenyl)-piperidin-4-yl]-2- 100   methyl-2,4,5,7-tetrahydro- 5   pyrazolo[3,4-d]pyrimidin-6-one (Example285) Ij-36 5-[1-(2-Ethyl-6-fluoro-phenyl)- C-3-2 BB-16-26 A 1.12 (I)516.35 piperidin-4-yl]-2-methyl-7-(2- 100   trifluoromethyl-benzyl)-2,4,5,7- 1  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 299) Ij-375-[1-(2-Difluoromethyl-6-fluoro- C-3-2 BB-16-27 A 1.18 (I) 538.35phenyl)-piperidin-4-yl]-2-methyl-7-(2- 100   trifluoromethyl-benzyl)-2,4,5,7- 1  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 300) Ij-386-[1-(2-Difluoromethyl-6-fluoro- C-3-4 BB-16-27 A 1.18 (I) 538.29phenyl)-piperidin-4-yl]-2-methyl-4-(2- 100   trifluoromethyl-benzyl)-2,4,6,7- 4  tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 301) Ij-406-[1-(2-Chloro-6-fluoro-phenyl)- C-3-4 BB-16-24 A 1.21 (I) 522.27piperidin-4-yl]-2-methyl-4-(2- 100    trifluoromethyl-benzyl)-2,4,6,7-4   tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 302) Ij-415-[1-(2-Cyclopropyl-6-fluoro-phenyl)- C-3-2 BB-16-28 A 1.21 (I) 528.35piperidin-4-yl]-2-methyl-7-(2- 100    trifluoromethyl-benzyl)-2,4,5,7-4   tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 303) Ij-426-[1-(2-Cyclopropyl-6-fluoro-phenyl)- C-3-4 BB-16-28 A 1.22 (I) 528.32piperidin-4-yl]-2-methyl-4-(2- 100    trifluoromethyl-benzyl)-2,4,6,7-2.5 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 304) Ij-437-(2-Cyclopropyl-benzyl)-5-[1-(2- C-3-6 BB-16-28 A 1.21 (I) 500.36cyclopropyl-6-fluoro-phenyl)- 100    piperidin-4-yl]-2-methyl-2,4,5,7-3   tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 307) Ij-447-(2-Cyclopropyl-benzyl)-5-[1-(2- C-3-6 BB-16-27 A 1.17 (I) 510.36difluoromethyl-6-fluoro-phenyl)- 100   piperidin-4-yl]-2-methyl-2,4,5,7- 3  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 308)

Method D (Multistep) Step A: Aromatic Nucleophilic Substitution

To a soln. of amine 0-3 (1 eq) and halide BB-16 (2 eq) in DMSO (3.4mL/mmol) was added CsF (2 eq). The rxn mixture was heated at a giventemperature for a given time under possible microwave irradiation (seeTable) and was partitioned between EtOAc and water. The org. phase waswashed with water and brine, dried over MgSO₄ and concentrated in vacuo.The crude was purified by CC using Hept/EtOAc.

TABLE 59 t_(R) [min] MS-data Reactant Reactant T [° C.] (LC/MS m/z Ij-AName C-3 BB-16 time [h] method) [M + H]⁺ Ij-17A1,3-Dimethyl-5-{4-[2-methyl-6-oxo-7-(2- C-3-2 BB-16-17 150 1.01 (I)516.21 trifluoromethyl-benzyl)-2,4,6,7-  3tetrahydro-pyrazolo[3,4-d]pyrimidin-5- microwaveyl]-piperidin-1-yl}-1H-pyrazole-4- carbaldehyde

Step B: Decarbonylation

To a soln. of Ij-A (1 eq) in MeOH (8 mL/mmol) was addedtoluene-4-sulfonic acid monohydrate (0.25 eq) and the rxn mixture washeated at 120° C. under microwave condition for a given time (seeTable). It was concentrated in vacuo and partitioned between EtOAc and asat. aq. soln. of NaHCO₃. The org. phase was washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude was purified by CC usingHept/EtOAc/MeOH.

TABLE 60 t_(R) [min] MS-data Reactant time (LC/MS- m/z Ij-B Name Ij-A[h] method) [M + H]⁺ Ij-17B5-[1-(2,5-Dimethyl-2H-pyrazol-3-yl)-piperidin-4-yl]- Ij-17A 9 0.86 (I)488.21 2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one

Step C: Chlorination

To a soln. of Ij-B (1 eq) in THE (5 mL/mmol) was added NCS (1.4 eq) andthe rxn mixture was stirred at RT for a given time (see Table). It waspartitioned between EtOAc and water and the org. phase was washed withbrine, dried over MgSO₄ and concentrated in vacuo. The crude waspurified by CC using Hept/EtOAc. When necessary an additionalpurification by prep. LC-MS using method 5 was performed.

TABLE 61 t_(R) [min] MS-data Reactant time (LC/MS m/z Ij Name Ij-B [h]method) [M + H]⁺ Ij-17 5-[1-(4-Chloro-2,5-dimethyl-2H-pyrazol-3-yl)-Ij-17B 0.5 1.11 (I) 522.17piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 238)

Chiral Separation of Compounds of Formula Ia, Ic or Ij

Racemates of formula Ia, Ic or Ij were separated into the respectiveenantiomers using preparative chiral HPLC or SFC (equipped with a givencolumn and eluting with given parameters (see Table), detection: UV 210nm).

Both enantiomers were characterized by analytical chiral HPLC or SFC(equipped with a given Daicel column and eluting with given parameters(see Table), detection: UV 210 to 280 nm).

The absolute configuration for the molecule Ik-70 (Example 324,enantiomer B) was assessed by single crystal X-ray diffraction (suitablecrystal obtained from iPrOH) and proved to be in absolute(R)-configuration. Consequently, the absolute configuration for themolecule Ik-69 (Example 323, enantiomer A) was assigned (S). In analogy,for all example compounds wherein R⁴ represents methyl listed in Table69 below, the enantiomer showing higher activity in the in vitrobiological assay disclosed below may be assumed to have the absolute(S)-configuration.

TABLE 62 Column Column t_(R) Racemate Eluent Flow Eluent Flow [min] IkName Ia, Ic or Ij (preparative) (analytical) chiral HPLC Ik-1 5-[(R)- or(S)-1-(2,6-Dimethyl- Ij-5 ChiralCel OD-H ChiralCel OD-H 5.97phenyl)-pyrrolidin-3-yl]-2-methyl- 20 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm7-(2-trifluoromethyl-benzyl)- Hept/(EtOH + 0.1% (Hept + 0.05%2,4,5,7-tetrahydro-pyrazolo[3,4- DEA) 70/30 DEA)/(EtOH + 0.05%d]pyrimidin-6-one (Enantiomer A) 16 mL/min DEA) 70/30 (Example 57) 0.8mL/min Ik-2 5-[(S)- or (R)-1-(2,6-Dimethyl- 8.36phenyl)-pyrrolidin-3-yl]-2-methyl- 7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 58) Ik-3 5-[1-(2-Fluoro-6-methyl-phenyl)- Ic-71 ChiralPak IDChiralPak ID 12.8 piperidin-4-yl]-2-((S)- or (R)-2- 20 × 250 mm, 5 μm4.6 × 250 mm, 5 μm fluoro-propyl)-7-(2-trifluoromethyl- Hept/(EtOH +0.1% (Hept + 0.02% benzyl)-2,4,5,7-tetrahydro- DEA) 90/10 DEA)/(EtOH +0.02% pyrazolo[3,4-d]pyrimidin-6-one 16 mL/min DEA) 90/10 (Enantiomer B)(Example 185) Ik-4 5-[1-(2-Fluoro-6-methyl-phenyl)- 0.8 mL/min 10.0piperidin-4-yl]-2-((R)- or (S)-2- fluoro-propyl)-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerA) (Example 186) Ik-5 2-((S)-or (R)-2,2-Difluoro-1- Ic-72 ChiralPak ICChiralPak IC 10.29 methyl-ethyl)-5-[1-(2-fluoro-6- 30 × 250 mm, 5 μm 4.6× 250 mm, 5 μm methyl-phenyl)-piperidin-4-yl]-7- Hept/(EtOH + 0.1%(Hept + 0.02% (2-trifluoromethyl-benzyl)-2,4,5,7- DEA) 90/10DEA)/(EtOH + 0.02% tetrahydro-pyrazolo[3,4- 34 mL/min DEA) 90/10d]pyrimidin-6-one (Enantiomer B) 0.8 mL/min (Example 187) Ik-6 2-((R)-or (S)-2,2-Difluoro-1- 8.49 methyl-ethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- (2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer A) (Example 188)Ik-7 2-((R)- or (S)-2,2-Difluoro- Ic-73 ChiralPak IG ChiralPak IG 8.12cyclopropylmethyl)-5-[1-(2-fluoro- 20 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm6-methyl-phenyl)-piperidin-4-yl]-7- Hept/(EtOH + 0.1% (Hept + 0.02%(2-trifluoromethyl-benzyl)-2,4,5,7- DEA) 70/30 DEA)/(EtOH + 0.02%tetrahydro-pyrazolo[3,4- 16 mL/min DEA) 70/30 d]pyrimidin-6-one(Enantiomer A) 0.8 mL/min (Example 189) Ik-8 2-((S)- or(R)-2,2-Difluoro- 9.87 cyclopropylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- (2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 190)Ik-9 (R)- or (S)-6-[1-(2-Fluoro-6- Ia-22 Chiralpak IA Chiralpak IA 1.73methyl-phenyl)-piperidin-4-yl]-2,7- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmdimethyl-4-(2-trifluoromethyl- CO₂/(2-propanol + CO₂/EtOH 85/15benzyl)-2,4,6,7-tetrahydro- 0.1% DEA) 90/10 4 mL/minpyrazolo[4,3-d]pyrimidin-5-one 160 mL/min 150 bars, 40° C. (EnantiomerA) (Example 202) 100 bars, 40° C. Ik-10 (S)- or (R)-6-[1-(2-Fluoro-6-2.02 methyl-phenyl)-piperidin-4-yl]-2,7- dimethyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (EnantiomerB) (Example 203) Ik-11 (R)- or (S)-5-[1-(2-Fluoro-6- Ia-26 Chiralpak ICChiralpak IC 1.81 methyl-phenyl)-piperidin-4-yl]-2,4- 30 × 250 mm, 5 μm4.6 × 250 mm, 5 μm dimethyl-7-(2-trifluoromethyl- CO₂/EtOH 80/20CO₂/EtOH 80/20 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 220) Ik-12 (S)- or (R)-5-[1-(2-Fluoro-6- 2.82methyl-phenyl)-piperidin-4-yl]-2,4- dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 221) Ik-13 5-[(S)- or (R)-1-(2-Fluoro-6- Ia-27 ChiralpakAD-H Chiralpak AD-H 3.69 methyl-phenyl)-azepan-4-yl]-2- 30 × 250 mm, 5μm 4.6 × 250 mm, 5 μm methyl-7-(2-trifluoromethyl- CO₂/EtOH 85/15CO₂/EtOH 85/15 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 225) Ik-14 5-[(R)- or (S)-1-(2-Fluoro-6- 2.77methyl-phenyl)-azepan-4-yl]-2- methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 226) Ik-15 5-[(R)- or (S)-1-(2-Fluoro-6- Ia-33 ChiralpakAD-H Chiralpak AD-H 1.40 methyl-phenyl)-3-methyl- 30 × 250 mm, 5 μm 4.6× 250 mm, 5 μm pyrrolidin-3-yl]-2-methyl-7-(2- CO₂/EtOH 80/20CO₂/(EtOH + trifluoromethyl-benzyl)-2,4,5,7- 160 mL/min 1% DEA) 85/15tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 4 mL/min d]pyrimidin-6-one(Enantiomer A) 150 bars, 40° C. (Example 234) Ik-16 5-[(S)- or(R)-1-(2-Fluoro-6- 1.82 methyl-phenyl)-3-methyl-pyrrolidin-3-yl]-2-methyl-7-(2- trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 235)Ik-17 5-[(R)- or (S)-1-(2-Fluoro-6- Ia-37 Chiralpak IF Chiralpak IF 2.07methyl-phenyl)-piperidin-3-yl]-2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmmethyl-7-(2-trifluoromethyl- CO₂/EtOH 75/25 CO₂/EtOH 75/25benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 241) Ik-18 5-[(S)- or (R)-1-(2-Fluoro-6- 2.70methyl-phenyl)-piperidin-3-yl]-2- methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 242) Ik-19 5-[1-(2-Fluoro-6-methyl-phenyl)- Ia-38 ChiralpakAZ-H Chiralpak AZ-H 1.88 piperidin-4-yl]-2-methyl-7-[(R)- or 30 × 250mm, 5 μm 4.6 × 250 mm, 5 μm (S)-1-(2-trifluoromethyl-phenyl)- CO₂/EtOH75/25 CO₂/EtOH 75/25 ethyl]-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 246) Ik-20 5-[1-(2-Fluoro-6-methyl-phenyl)- 2.63piperidin-4-yl]-2-methyl-7-[(S)- or (R)-1-(2-trifluoromethyl-phenyl)-ethyl]-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B)(Example 247) Ik-21 (R)- or (S)-2-(2,2-Difluoro-propyl)- Ic-93 Regis(R,R) Regis (R,R) 1.57 6-[1-(2-fluoro-6-methyl-phenyl)- Whelk-O1Whelk-O1 piperidin-4-yl]-7-methyl-4-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm,5 μm trifluoromethyl-benzyl)-2,4,6,7- CO₂/(MeCN/EtOH CO₂/(MeCN/EtOHtetrahydro-pyrazolo[4,3- 1/1) 70/30 1/1) 70/30 d]pyrimidin-5-one(Enantiomer A) 160 mL/min 4 mL/min (Example 253) 100 bars, 40° C. 150bars, 40° C. Ik-22 (S)- or (R)-2-(2,2-Difluoro-propyl)- 2.096-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) (Example 254) Ik-23 (R)- or(S)-1-(2,2-Difluoro-propyl)- Id-9 Regis (R,R) Regis (R,R) 1.696-[1-(2-fluoro-6-methyl-phenyl)- Whelk-O1 Whelk-O1piperidin-4-yl]-7-methyl-4-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmtrifluoromethyl-benzyl)-1,4,6,7- CO₂/(MeCN/EtOH CO₂/(MeCN/EtOHtetrahydro-pyrazolo[4,3- 1/1) 70/30 1/1) 70/30 d]pyrimidin-5-one(Enantiomer A) 160 mL/min 4 mL/min (Example 255) 100 bars, 40° C. 150bars, 40° C. Ik-24 (S)- or (R)-1-(2,2-Difluoro-propyl)- 2.216-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-1,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) (Example 256) Ik-256-[1-(2-Fluoro-6-methyl-phenyl)- Ia-44 Chiralpak IG Chiralpak IG 1.88piperidin-4-yl]-2-methyl-4-[(R)- or 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm(S)-1-(2-trifluoromethyl-phenyl)- CO₂/EtOH 70/30 CO₂/EtOH 70/30ethyl]-2,4,6,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[4,3-d]pyrimidin-5-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 261) Ik-26 6-[1-(2-Fluoro-6-methyl-phenyl)- 2.42piperidin-4-yl]-2-methyl-4-[(S)- or (R)-1-(2-trifluoromethyl-phenyl)-ethyl]-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B)(Example 262) Ik-27 (R)- or (S)-6-[1-(2-Fluoro-6- Ib-10 Regis (R,R)Regis (R,R) 1.74 methyl-phenyl)-piperidin-4-yl]-7- Whelk-O1 Whelk-O1methyl-4-(2-trifluoromethyl- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmbenzyl)-2,4,6,7-tetrahydro- CO₂/EtOH 60/40 CO₂/EtOH 60/40pyrazolo[4,3-d]pyrimidin-5-one 160 mL/min 4 mL/min (Enantiomer A)(Example 263) 100 bars, 40° C. 150 bars, 40° C. Ik-28 (S)- or(R)-6-[1-(2-Fluoro-6- 2.30 methyl-phenyl)-piperidin-4-yl]-7-methyl-4-(2-trifluoromethyl- benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) Ik-29 (R)- or(S)-2-Cyclopropyl-6-[1-(2- Ic-94 Regis (R,R) Regis (R,R) 1.90fluoro-6-methyl-phenyl)-piperidin- Whelk-O1 Whelk-O14-yl]-7-methyl-4-(2-trifluoromethyl- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5μm benzyl)-2,4,6,7-tetrahydro- CO₂/(MeCN/EtOH CO₂/(MeCN/EtOHpyrazolo[4,3-d]pyrimidin-5-one 1/1) 70/30 1/1) 70/30 (Enantiomer A)(Example 265) 160 mL/min 4 mL/min 100 bars, 40° C. 150 bars, 40° C.Ik-30 (S)- or (R)-2-Cyclopropyl-6-[1-(2- 2.48fluoro-6-methyl-phenyl)-piperidin- 4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (EnantiomerB) (Example 266) Ik-31 (R)- or (S)-4-(2-Cyclopropyl- Ib-11 Chiralpak IBChiralpak IB 2.16 benzyl)-6-(2′-methoxy-4′-methyl- 30 × 250 mm, 5 μm 4.6× 250 mm, 5 μm 3,4,5,6-tetrahydro-2H- CO₂/EtOH 75/25 CO₂/EtOH 75/25[1,3′]bipyridinyl-4-yl)-7-methyl- 160 mL/min 4 mL/min2,4,6,7-tetrahydro-pyrazolo[4,3- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-5-one (Enantiomer A) Ik-32 (S)- or (R)-4-(2-Cyclopropyl-2.80 benzyl)-6-(2′-methoxy-4′-methyl- 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl- 2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) (Example 274) Ik-33 (R)- or(S)-4-(2-Cyclopropyl- Ib-12 Chiralpak IB Chiralpak IB 2.16benzyl)-6-[1-(2-fluoro-6-methyl- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmphenyl)-piperidin-4-yl]-7-methyl- CO₂/EtOH 70/30 CO₂/EtOH 75/252,4,6,7-tetrahydro-pyrazolo[4,3- 160 mL/min 4 mL/min d]pyrimidin-5-one(Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. Ik-34 (S)- or(R)-4-(2-Cyclopropyl- 3.06 benzyl)-6-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-methyl- 2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) (Example 275) Ik-35 (R)- or(S)-4-(2-Cyclopropyl- Ic-95 Chiralpak IB Chiralpak IB 1.56benzyl)-2-(2,2-difluoro-propyl)-6- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm[1-(2-fluoro-6-methyl-phenyl)- CO₂/EtOH 80/20 CO₂/EtOH 80/20piperidin-4-yl]-7-methyl-2,4,6,7- 160 mL/min 4 mL/mintetrahydro-pyrazolo[4,3- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-5-one (Enantiomer A) (Example 276) Ik-36 (S)- or(R)-4-(2-Cyclopropyl- 2.32 benzyl)-2-(2,2-difluoro-propyl)-6-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) (Example 277)Ik-37 (R)- or (S)-2-Cyclopropyl-4-(2- Ic-96 Chiralpak IB Chiralpak IB1.74 cyclopropyl-benzyl)-6-[1-(2-fluoro- 30 × 250 mm, 5 μm 4.6 × 250 mm,5 μm 6-methyl-phenyl)-piperidin-4-yl]-7- CO₂/EtOH 75/25 CO₂/EtOH 75/25methyl-2,4,6,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[4,3-d]pyrimidin-5-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 278) Ik-38 (S)- or (R)-2-Cyclopropyl-4-(2- 2.42cyclopropyl-benzyl)-6-[1-(2-fluoro- 6-methyl-phenyl)-piperidin-4-yl]-7-methyl-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B)(Example 279) Ik-39 5-(2′-Methoxy-4′-methyl-3,4,5,6- Ij-27 Regis (R,R)Regis (R,R) 2.12 tetrahydro-2H-[1,3′]bipyridinyl-4- Whelk-O1 Whelk-O1yl)-2-methyl-7-[(R)- or (S)-1-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmtrifluoromethyl-phenyl)-ethyl]- CO₂/EtOH 70/30 CO₂/EtOH 70/302,4,5,7-tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/min d]pyrimidin-6-one(Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 286) Ik-405-(2′-Methoxy-4′-methyl-3,4,5,6- 2.66 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2-methyl-7-[(S)- or (R)-1-(2- trifluoromethyl-phenyl)-ethyl]-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 287) Ik-41 3-Fluoro-2-(4-{2-methyl-6-oxo-7- Ij-28 Regis (R,R)Regis (R,R) 2.81 [(R)- or (S)-1-(2-trifluoromethyl- Whelk-O1 Whelk-O1phenyl)-ethyl]-2,4,6,7-tetrahydro- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmpyrazolo[3,4-d]pyrimidin-5-yl}- CO₂/EtOH 75/25 CO₂/EtOH 75/25piperidin-1-yl)-benzonitrile 160 mL/min 4 mL/min (Enantiomer A) (Example288) 100 bars, 40° C. 150 bars, 40° C. Ik-423-Fluoro-2-(4-{2-methyl-6-oxo-7- 3.32 [(S)- or (R)-1-(2-trifluoromethyl-phenyl)-ethyl]-2,4,6,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-5-yl}-piperidin-1-yl)-benzonitrile (Enantiomer B) (Example 289) Ik-435-[1-(2,6-Difluoro-phenyl)- Ij-29 Regis (R,R) Regis (R,R) 2.61piperidin-4-yl]-2-methyl-7-[(R)- or Whelk-O1 Whelk-O1(S)-1-(2-trifluoromethyl-phenyl)- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmethyl]-2,4,5,7-tetrahydro- CO₂/EtOH 80/20 CO₂/EtOH 80/20pyrazolo[3,4-d]pyrimidin-6-one 160 mL/min 4 mL/min (Enantiomer A)(Example 290) 100 bars, 40° C. 150 bars, 40° C. Ik-445-[1-(2,6-Difluoro-phenyl)- 3.11 piperidin-4-yl]-2-methyl-7-[(S)- or(R)-1-(2-trifluoromethyl-phenyl)- ethyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 291) Ik-45 (R)-or (S)-2-Cyclopropyl-4-(2- Ic-97 Chiralpak AD-H Chiralpak AD-H 1.42cyclopropyl-benzyl)-6-(2′- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmmethoxy-4′-methyl-3,4,5,6- CO₂/EtOH 70/30 CO₂/EtOH 70/30tetrahydro-2H-[1,3′]bipyridinyl-4- 160 mL/min 4 mL/minyl)-7-methyl-2,4,6,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C.pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer A) (Example 293) Ik-46 (S)-or (R)-2-Cyclopropyl-4-(2- 1.97 cyclopropyl-benzyl)-6-(2′-methoxy-4′-methyl-3,4,5,6- tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-methyl-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one(Enantiomer B) (Example 292) Ik-47 (R)- or (S)-6-(2′-Methoxy-4′- Ib-14Regis (R,R) Regis (R,R) 1.80 methyl-3,4,5,6-tetrahydro-2H- Whelk-O1Whelk-O1 [1,3′]bipyridinyl-4-yl)-7-methyl-4- 30 × 250 mm, 5 μm 4.6 × 250mm, 5 μm (2-trifluoromethyl-benzyl)-2,4,6,7- CO₂/(MeCN/EtOHCO₂/(MeCN/EtOH tetrahydro-pyrazolo[4,3- 1/1) 65/35 1/1) 65/35d]pyrimidin-5-one (Enantiomer A) 160 mL/min 4 mL/min (Example 295) 100bars, 40° C. 150 bars, 40° C. Ik-48 (S)- or (R)-6-(2′-Methoxy-4′- 2.50methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) Ik-49 (R)- or (S)-2-Cyclopropyl-6-(2′-Ic-98 Chiralpak IE Chiralpak IE 1.89 methoxy-4′-methyl-3,4,5,6- 30 × 250mm, 5 μm 4.6 × 250 mm, 5 μm tetrahydro-2H-[1,3′]bipyridinyl-4- CO₂/EtOH65/35 CO₂/EtOH 65/35 yl)-7-methyl-4-(2-trifluoromethyl- 160 mL/min 4mL/min benzyl)-2,4,6,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C.pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer A) (Example 296) Ik-50 (S)-or (R)-2-Cyclopropy l-6-(2′- 2.39 methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4- yl)-7-methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (EnantiomerB) (Example 297) Ik-51 (R)- or (S)-6-(2′-Methoxy-4′- Ic-99 Chiralpak IEChiralpak IE 2.56 methyl-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 ×250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-2,7-dimethyl- CO₂/EtOH 75/25CO₂/EtOH 75/25 4-(2-trifluoromethyl-benzyl)- 160 mL/min 4 mL/min2,4,6,7-tetrahydro-pyrazolo[4,3- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-5-one (Enantiomer A) (Example 298) Ik-52 (S)- or(R)-6-(2′-Methoxy-4′- 3.19 methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,7-dimethyl- 4-(2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) Ik-53(R)- or (S)-2-(2,2-Difluoro-propyl)- Ic-100 Regis (R,R) Regis (R,R) 2.245-[1-(2-fluoro-6-methyl-phenyl)- Whelk-O1 Whelk-O1piperidin-4-yl]-4-methyl-7-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmtrifluoromethyl-benzyl)-2,4,5,7- CO₂/EtOH 70/30 CO₂/EtOH 70/30tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/min d]pyrimidin-6-one(Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 305) Ik-54(S)- or (R)-2-(2,2-Difluoro-propyl)- 2.765-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 306) Ik-55 (R)- or(S)-2-Cyclopropyl-5-[1-(2- Ia-55 Chiralpak IC Chiralpak IC 1.19fluoro-6-methyl-phenyl)-piperidin- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm4-yl]-4-methyl-7-(2-trifluoromethyl- CO₂/EtOH 65/35 CO₂/EtOH 65/35benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 309) Ik-56 (S)- or (R)-2-Cyclopropyl-5-[1-(2-1.59 fluoro-6-methyl-phenyl)-piperidin-4-yl]-4-methyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 310) Ik-57 (R)-or (S)-2-Cyclopropyl-5-[1-(2- Ia-56 Chiralpak IC Chiralpak IC 1.22difluoromethyl-6-fluoro-phenyl)- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmpiperidin-4-yl]-4-methyl-7-(2- CO₂/EtOH 75/25 CO₂/EtOH 75/25trifluoromethyl-benzyl)-2,4,5,7- 160 mL/min 4 mL/mintetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 311) Ik-58 (S)- or(R)-2-Cyclopropyl-5-[1-(2- 1.62 difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2- trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 312)Ik-59 (R)- or (S)-5-[1-(2-Difluoromethyl- Ia-57 Chiralpak IC ChiralpakIC 1.33 6-fluoro-phenyl)-piperidin-4-yl]- 30 × 250 mm, 5 μm 4.6 × 250mm, 5 μm 2,4-dimethyl-7-(2-trifluoromethyl- CO₂/EtOH 80/20 CO₂/EtOH80/20 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 314) Ik-60 (S)- or (R)-5-[1-(2-Difluoromethyl-1.80 6-fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 315) Ik-61 (R)-or (S)-5-[1-(2-Fluoro-6- Ib-13 Chiralpak AD-H Chiralpak AD-H 0.86methyl-phenyl)-piperidin-4-yl]-4- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmmethyl-7-(2-trifluoromethyl- CO₂/EtOH 55/45 CO₂/EtOH 55/45benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) Ik-62 (S)- or (R)-5-[1-(2-Fluoro-6- 1.20methyl-phenyl)-piperidin-4-yl]-4- methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 316) Ik-63 (R)- or (S)-7-(2-Cyclopropyl- Ia-58 ChiralpakAD-H Chiralpak AD-H 1.75 benzyl)-5-[1-(2-fluoro-6-methyl- 30 × 250 mm, 5μm 4.6 × 250 mm, 5 μm phenyl)-piperidin-4-yl]-2,4- CO₂/EtOH 70/30CO₂/EtOH 70/30 dimethyl-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 317) Ik-64 (S)- or (R)-7-(2-Cyclopropyl- 2.32benzyl)-5-[1-(2-fluoro-6-methyl- phenyl)-piperidin-4-yl]-2,4-dimethyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 318) Ik-65 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ia-59Chiralpak IC Chiralpak IC 1.32 phenyl)-piperidin-4-yl]-2,4- 30 × 250 mm,5 μm 4.6 × 250 mm, 5 μm dimethyl-7-(2-trifluoromethyl- CO₂/EtOH 70/30CO₂/EtOH 70/30 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 319) Ik-66 (S)- or (R)-5-[1-(2-Chloro-6-fluoro-1.78 phenyl)-piperidin-4-yl]-2,4- dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 320) Ik-67 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ia-60Chiralpak IB Chiralpak IB 1.97 phenyl)-piperidin-4-yl]-7-(2- 30 × 250mm, 5 μm 4.6 × 250 mm, 5 μm cyclopropyl-benzyl)-2,4-dimethyl- CO₂/EtOH70/30 CO₂/EtOH 70/30 2,4,5,7-tetrahydro-pyrazolo[3,4- 160 mL/min 4mL/min d]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40°C. (Example 321) Ik-68 (S)- or (R)-5-[1-(2-Chloro-6-fluoro- 2.46phenyl)-piperidin-4-yl]-7-(2- cyclopropyl-benzyl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 322) Ik-69 (S)-7-(2-Cyclopropyl-benzyl)-5-[1- Ia-61 ChiralpakAD-H Chiralpak AD-H 1.34 (2-difluoromethyl-6-fluoro-phenyl)- 30 × 250mm, 5 μm 4.6 × 250 mm, 5 μm piperidin-4-yl]-2,4-dimethyl- CO₂/EtOH 75/25CO₂/EtOH 70/30 2,4,5,7-tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/mind]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C.(Example 323) Ik-70 (R)-7-(2-Cyclopropyl-benzyl)-5-[1- 1.70(2-difluoromethyl-6-fluoro-phenyl)- piperidin-4-yl]-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 324) Ik-71 (R)- or (S)-7-(2-Cyclopropyl- Ia-62 Chiralpak AD-HChiralpak AD-H 1.59 benzyl)-5-[1-(2-cyclopropyl-6- 30 × 250 mm, 5 μm 4.6× 250 mm, 5 μm fluoro-phenyl)-piperidin-4-yl]-2,4- CO₂/EtOH 70/30CO₂/EtOH 70/30 dimethyl-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 325) Ik-72 (S)- or (R)-7-(2-Cyclopropyl- 2.16benzyl)-5-[1-(2-cyclopropyl-6- fluoro-phenyl)-piperidin-4-yl]-2,4-dimethyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 326) Ik-73 (R)- or (S)-6-[1-(2-Chloro-6-fluoro- Ic-101Chiralpak AD-H Chiralpak AD-H 1.93 phenyl)-piperidin-4-yl]-2- 30 × 250mm, 5 μm 4.6 × 250 mm, 5 μm cyclopropyl-7-methyl-4-(2- CO₂/EtOH 85/15CO₂/EtOH 85/15 trifluoromethyl-benzyl)-2,4,6,7- 160 mL/min 4 mL/mintetrahydro-pyrazolo[4,3- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-5-one (Enantiomer A) (Example 327) Ik-74 (S)- or(R)-6-[1-(2-Chloro-6-fluoro- 2.51 phenyl)-piperidin-4-yl]-2-cyclopropyl-7-methyl-4-(2- trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) (Example 328)Ik-75 (R)- or (S)-2-Cyclopropyl-6-[1-(2- Ic-102 Regis (R,R) Regis (R,R)1.82 difluoromethyl-6-fluoro-phenyl)- Whelk-O1 Whelk-O1piperidin-4-yl]-7-methyl-4-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmtrifluoromethyl-benzyl)-2,4,6,7- CO₂/EtOH 65/35 CO₂/EtOH 65/35tetrahydro-pyrazolo[4,3- 160 mL/min 4 mL/min d]pyrimidin-5-one(Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 329) Ik-76(S)- or (R)-2-Cyclopropyl-6-[1-(2- 2.47 difluoromethyl-6-fluoro-phenyl)-piperidin-4-yl]-7-methyl-4-(2- trifluoromethyl-benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) (Example 330)Ik-77 (R)- or (S)-5-(2′-Methoxy-4′- Ia-65 Chiralpak IC Chiralpak IC 1.22methyl-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm[1,3′]bipyridinyl-4-yl)-2,4-dimethyl- CO₂/EtOH 60/40 CO₂/EtOH 60/407-(2-trifluoromethyl-benzyl)- 160 mL/min 4 mL/min2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 331) Ik-78 (S)- or(R)-5-(2′-Methoxy-4′- 1.78 methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 332) Ik-79 (R)- or (S)-5-[1-(2-Cydopropyl-6- Ia-66 Chiralpak ICChiralpak IC 1.55 fluoro-phenyl)-piperidin-4-yl]-2,4- 30 × 250 mm, 5 μm4.6 × 250 mm, 5 μm dimethyl-7-(2-trifluoromethyl- CO₂/EtOH 75/25CO₂/EtOH 75/25 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 333) Ik-80 (S)- or (R)-5-[1-(2-Cyclopropyl-6-2.18 fluoro-phenyl)-piperidin-4-yl]-2,4- dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 334) Ik-81 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ia-67Chiralpak IC Chiralpak IC 1.41 phenyl)-piperidin-4-yl]-2- 30 × 250 mm, 5μm 4.6 × 250 mm, 5 μm cyclopropyl-4-methyl-7-(2- CO₂/EtOH 70/30 CO₂/EtOH70/30 trifluoromethyl-benzyl)-2,4,5,7- 160 mL/min 4 mL/mintetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 335) Ik-82 (S)- or(R)-5-[1-(2-Chloro-6-fluoro- 2.01 phenyl)-piperidin-4-yl]-2-cyclopropyl-4-methyl-7-(2- trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 336)Ik-83 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ia-69 Chiralpak AD-HChiralpak AD-H 1.24 phenyl)-piperidin-4-yl]-2- 30 × 250 mm, 5 μm 4.6 ×250 mm, 5 μm cydopropyl-7-(2-cyclopropyl- CO₂/EtOH 50/50 CO₂/EtOH 50/50benzyl)-4-methyl-2,4,5,7- 160 mL/min 4 mL/min tetrahydro-pyrazolo[3,4-100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A)(Example 337) Ik-84 (S)- or (R)-5-[1-(2-Chloro-6-fluoro- 1.81phenyl)-piperidin-4-yl]-2- cyclopropyl-7-(2-cyclopropyl-benzyl)-4-methyl-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one(Enantiomer B) (Example 338) Ik-85 (R)- or (S)-2-Cyclopropyl-7-(2- Ia-68Chiralpak AD-H Chiralpak AD-H 1.07 cyclopropyl-benzyl)-5-[1-(2-fluoro-30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm 6-methyl-phenyl)-piperidin-4-yl]-4-CO₂/EtOH 50/50 CO₂/EtOH 50/50 methyl-2,4,5,7-tetrahydro- 160 mL/min 4mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 339) Ik-86 (S)- or (R)-2-Cyclopropyl-7-(2- 1.55cyclopropyl-benzyl)-5-[1-(2-fluoro- 6-methyl-phenyl)-piperidin-4-yl]-4-methyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B)(Example 340) Ik-87 (R)- or (S)-2-Cyclopropyl-5-(2′- Ia-70 Chiralpak ICChiralpak IC 1.47 methoxy-4′-methyl-3,4,5,6- 30 × 250 mm, 5 μm 4.6 × 250mm, 5 μm tetrahydro-2H-[1,3′]bipyridinyl-4- CO₂/EtOH 65/35 CO₂/EtOH65/35 yl)-4-methyl-7-(2-trifluoromethyl- 160 mL/min 4 mL/minbenzyl)-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C.pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 344) Ik-88 (S)-or (R)-2-Cyclopropyl-5-(2′- 2.42 methoxy-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4- yl)-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 345) Ik-89 (R)- or (S)-5-(4′-Difluoromethyl-2′- Ia-71Chiralpak IC Chiralpak IC 1.45 methoxy-3,4,5,6-tetrahydro-2H- 30 × 250mm, 5 μm 4.6 × 250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-2,4-dimethyl-CO₂/EtOH 80/20 CO₂/EtOH 80/20 7-(2-trifluoromethyl-benzyl)- 160 mL/min 4mL/min 2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40°C. d]pyrimidin-6-one (Enantiomer A) (Example 346) Ik-90 (S)- or(R)-5-(4′-Difluoromethyl-2′- 2.28 methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 347) Ik-91 (R)- or (S)-5-[1-(2-Difluoromethyl- Ib-17 ChiralCelOZ-H ChiralCel OZ-H 0.91 6-fluoro-phenyl)-piperidin-4-yl]-4- 30 × 250mm, 5 μm 4.6 × 250 mm, 5 μm methyl-7-(2-trifluoromethyl- CO₂/EtOH 60/40CO₂/EtOH 60/40 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/minpyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C.(Enantiomer A) (Example 348) Ik-92 (S)- or (R)-5-[1-(2-Difluoromethyl-1.37 6-fluoro-phenyl)-piperidin-4-yl]-4- methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 349) Ik-93 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ib-18ChiralCel OZ-H ChiralCel OZ-H 0.93 phenyl)-piperidin-4-yl]-4-methyl-7-30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm (2-trifluoromethyl-benzyl)-2,4,5,7-CO₂/EtOH 50/50 CO₂/EtOH 50/50 tetrahydro-pyrazolo[3,4- 160 mL/min 4mL/min d]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40°C. (Example 350) Ik-94 (S)- or (R)-5-[1-(2-Chloro-6-fluoro- 1.53phenyl)-piperidin-4-yl]-4-methyl-7- (2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 351)Ik-95 (R)- or (S)-5-(4′-Difluoromethyl-2′- Ib-19 ChiralCel OZ-HChiralCel OZ-H 0.93 methoxy-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6× 250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-4-methyl-7- CO₂/EtOH 60/40CO₂/EtOH 60/40 (2-trifluoromethyl-benzyl)-2,4,5,7- 160 mL/min 4 mL/mintetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 352) Ik-96 (S)- or(R)-5-(4′-Difluoromethyl-2′- 1.42 methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-7- (2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 353)Ik-97 (R)- or (S)-5-[1-(2-Fluoro-6- Ia-75 Chiralpak IC Chiralpak IC 0.98methyl-phenyl)-piperidin-4-yl]-2,4- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μmdimethyl-7-(3-trifluoromethyl- CO₂/EtOH 50/50 CO₂/EtOH 50/50pyridin-2-ylmethyl)-2,4,5,7- 160 mL/min 4 mL/mintetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 354) Ik-98 (S)-or(R)-5-[1-(2-Fluoro-6- 1.37 methyl-phenyl)-piperidin-4-yl]-2,4-dimethyl-7-(3-trifluoromethyl- pyridin-2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 355)Ik-99 (R)- or (S)-5-(2′-Methoxy-4′- Ia-76 Chiralpak IC Chiralpak IC 1.11methyl-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm[1,3′]bipyridinyl-4-yl)-2,4-dimethyl- CO₂/EtOH 50/50 CO₂/EtOH 50/507-(3-trifluoromethyl-pyridin-2- 160 mL/min 4 mL/minylmethyl)-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C.pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 356) Ik-100 (S)-or (R)-5-(2′-Methoxy-4′- 2.02 methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 7-(3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 357) Ik-101 (R)- or (S)-2-Cyclopropyl-5-(4′- Ia-77 ChiralpakIC Chiralpak IC 1.19 difluoromethyl-2′-methoxy-3,4,5,6- 30 × 250 mm, 5μm 4.6 × 250 mm, 5 μm tetrahydro-2H-[1,3′]bipyridinyl-4- CO₂/EtOH 70/30CO₂/EtOH 70/30 yl)-4-methyl-7-(2-trifluoromethyl- 160 mL/min 4 mL/minbenzyl)-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C.pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 358) Ik-102 (S)-or (R)-2-Cyclopropyl-5-(4′- 1.66 difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4- yl)-4-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 359) Ik-103 (R)- or (S)-5-[1-(2-Bromo-6-fluoro- Ia-78Chiralpak IC Chiralpak IC 1.34 phenyl)-piperidin-4-yl]-2- 30 × 250 mm, 5μm 4.6 × 250 mm, 5 μm cyclopropyl-4-methyl-7-(2- CO₂/EtOH 65/35 CO₂/EtOH65/35 trifluoromethyl-benzyl)-2,4,5,7- 160 mL/min 4 mL/mintetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 360) Ik-104 (S)- or(R)-5-[1-(2-Bromo-6-fluoro- 1.86 phenyl)-piperidin-4-yl]-2-cyclopropyl-4-methyl-7-(2- trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 361)Ik-105 (R)- or (S)-5-(2′-Methoxy-4′- Ia-79 Chiralpak IC Chiralpak IC1.03 trifluoromethyl-3,4,5,6-tetrahydro- 30 × 250 mm, 5 μm 4.6 × 250 mm,5 μm 2H-[1,3′]bipyridinyl-4-yl)-2,4- CO₂/EtOH 70/30 CO₂/EtOH 70/30dimethyl-7-(2-trifluoromethyl- 160 mL/min 4 mL/minbenzyl)-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C.pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 362) Ik-106 (S)-or (R)-5-(2′-Methoxy-4′- 1.37 trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4- dimethyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 363) Ik-107 (R)- or (S)-7-(2-Cydopropyl- Ia-81 ChiralpakAD-H Chiralpak AD-H 0.99 benzyl)-5-(4′-difluoromethyl-2′- 30 × 250 mm, 5μm 4.6 × 250 mm, 5 μm methoxy-3,4,5,6-tetrahydro-2H- CO₂/EtOH 60/40CO₂/EtOH 60/40 [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 160 mL/min 4 mL/min2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 366) Ik-108 (S)- or(R)-7-(2-Cyclopropyl- 1.33 benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 367) Ik-109 (R)- or (S)-7-(2-Cydopropyl- Ia-80 Chiralpak AD-HChiralpak AD-H 0.99 benzyl)-5-(2′-methoxy-4′-methyl- 30 × 250 mm, 5 μm4.6 × 250 mm, 5 μm 3,4,5,6-tetrahydro-2H- CO₂/EtOH 50/50 CO₂/EtOH 50/50[1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 160 mL/min 4 mL/min2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 368) Ik-110 (S)- or(R)-7-(2-Cyclopropyl- 1.39 benzyl)-5-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 369) Ik-111 (R)- or (S)-7-(2-Cyclopropyl- Ib-20 Chiralpak IFChiralpak IF 1.52 benzyl)-5-(4′-difluoromethyl-2′- 30 × 250 mm, 5 μm 4.6× 250 mm, 5 μm methoxy-3,4,5,6-tetrahydro-2H- CO₂/EtOH 65/35 CO₂/EtOH65/35 [1,3′]bipyridinyl-4-yl)-4-methyl- 160 mL/min 4 mL/min2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 370) Ik-112 (S)- or(R)-7-(2-Cyclopropyl- 1.94 benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 371) Ik-113 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ib-21Chiralpak IF Chiralpak IF 1.54 phenyl)-piperidin-4-yl]-7-(2- 30 × 250mm, 5 μm 4.6 × 250 mm, 5 μm cyclopropyl-benzyl)-4-methyl- CO₂/EtOH 55/45CO₂/EtOH 55/45 2,4,5,7-tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/mind]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C.(Example 372) Ik-114 (S)- or (R)-5-[1-(2-Chloro-6-fluoro- 2.05phenyl)-piperidin-4-yl]-7-(2- cyclopropyl-benzyl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 373) Ik-115 (R)- or (S)-7-(2-Cyclopropyl- Ia-84 Chiralpak AD-HChiralpak AD-H 0.90 benzyl)-5-(2′-methoxy-4′- 30 × 250 mm, 5 μm 4.6 ×250 mm, 5 μm trifluoromethyl-3,4,5,6-tetrahydro- CO₂/EtOH 60/40 CO₂/EtOH60/40 2H-[1,3′]bipyridinyl-4-yl)-2,4- 160 mL/min 4 mL/mindimethyl-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C.pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 374) Ik-116 (S)-or (R)-7-(2-Cyclopropyl- 1.26 benzyl)-5-(2′-methoxy-4′-trifluoromethyl-3,4,5,6-tetrahydro- 2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (EnantiomerB) (Example 375) Ik-117 (R)- or (S)-5-(4′-Chloro-2′- Ia-85 Chiralpak ICChiralpak IC 1.10 methoxy-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 ×250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- CO₂/EtOH 55/45CO₂/EtOH 55/45 7-(2-trifluoromethyl-benzyl)- 160 mL/min 4 mL/min2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 376) Ik-118 (S)- or(R)-5-(4′-Chloro-2′- 1.48 methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 7-(2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 377) Ik-119 (R)- or (S)-5-(4′-Chloro-2′- Ia-86 Chiralpak AD-HChiralpak AD-H 1.23 methoxy-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6× 250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-7-(2- CO₂/EtOH 55/45 CO₂/EtOH55/45 cyclopropyl-benzyl)-2,4-dimethyl- 150 mL/min 4 mL/min2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C.d]pyrimidin-6-one (Enantiomer A) (Example 378) Ik-120 (S)- or(R)-5-(4′-Chloro-2′- 1.71 methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2- cyclopropyl-benzyl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 379) Ik-121 (R)- or (S)-2-Cyclopropyl-7-(2- Ia-87 ChiralpakAD-H Chiralpak AD-H 1.00 cyclopropyl-benzyl)-5-(2′- 30 × 250 mm, 5 μm4.6 × 250 mm, 5 μm methoxy-4′-methyl-3,4,5,6- CO₂/EtOH 50/50 CO₂/EtOH50/50 tetrahydro-2H-[1,3′]bipyridinyl-4- 160 mL/min 4 mL/minyl)-4-methyl-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C.pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 380) Ik-122 (S)-or (R)-2-Cyclopropyl-7-(2- 1.57 cyclopropyl-benzyl)-5-(2′-methoxy-4′-methyl-3,4,5,6- tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one(Enantiomer B) (Example 381) Ik-123 (R)- or (S)-2-Cyclopropyl-7-(2-Ia-88 Chiralpak AD-H Chiralpak AD-H 0.94 cyclopropyl-benzyl)-5-(4′- 30 ×250 mm, 5 μm 4.6 × 250 mm, 5 μm difluoromethyl-2′-methoxy-3,4,5,6-CO₂/EtOH 55/45 CO₂/EtOH 55/45 tetrahydro-2H-[1,3′]bipyridinyl-4- 160mL/min 4 mL/min yl)-4-methyl-2,4,5,7-tetrahydro- 100 bars, 40° C. 150bars, 40° C. pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 382)Ik-124 (S)- or (R)-2-Cyclopropyl-7-(2- 1.33 cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′-methoxy-3,4,5,6- tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one(Enantiomer B) (Example 383) Ik-125 (R)- or (S)-5-[1-(2-Bromo-6-fluoro-Ia-89 Chiralpak IF Chiralpak IF 1.96 phenyl)-piperidin-4-yl]-7-(2- 30 ×250 mm, 5 μm 4.6 × 250 mm, 5 μm cyclopropyl-benzyl)-2,4-dimethyl-CO₂/EtOH 50/50 CO₂/EtOH 55/45 2,4,5,7-tetrahydro-pyrazolo[3,4- 160mL/min 4 mL/min d]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150bars, 40° C. (Example 384) Ik-126 (S)- or (R)-5-[1-(2-Bromo-6-fluoro-2.77 phenyl)-piperidin-4-yl]-7-(2- cyclopropyl-benzyl)-2,4-dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B)(Example 385)

II. Biological Assays

In Vitro Assay

Adherent cells (CHO-K1 C5AR1 beta-arrestin cell line, DiscoverX, CA USA)are washed with PBS, detached by incubation with Dissociation Buffer(Gibco Cat #13151-014, 2 ml per 165 cm2 dish) for 3 minutes, then washedwith 10 ml PBS (without Mg++ and Ca++) and counted. 7500 cells/384-wellare seeded out in 384-well plates (Cell culture plate MTP384 whitePolystyrene, Corning, Cat #3570) in 20 μl/well Cell plating medium (F12HAMs/10% FCS/1% P/S) and incubated at 37° C./5% CO2/24 h.

5 μl Antagonist at 6-fold end concentration or DMSO control is added toassay medium and subsequently 5 μl 1-10 nM C5a agonist at 6 fold endconcentration. Cells are centrifuged for 1 min at 1000 rpm and incubatedfor 1.5 hour in at 37° C. Plates are equilibrated at room temperaturefor several minutes before adding 12 μl/well Detection Reagent(PathHunter Detection Kit, DiscoverX, Cat #93-0001). Plates arecentrifuged for 1 min at 1000 rpm and incubated for 45 minutes at RTbefore being measured on a Fluostar Optima, BMG Labtech. IC₅₀ values arecalculated from a serial dilution range of antagonist using inhousesoftware and given in nmol/l.

The calculated IC₅₀ values may fluctuate depending on the daily cellularassay performance. Fluctuations of this kind are known to those skilledin the art. Average IC₅₀ values from several measurements are given asgeometric mean values.

Antagonistic activities of exemplified compounds are displayed in Table.

TABLE 70 list of examples and their antagonistic activities C5aR ExampleCompound IC₅₀ Number No (nM) 1 Ia-1A 85 2 Ib-1 10 3 Ic-2 36 4 Id-1 293 5Ia-2 16 6 Ib-2 9 7 Ic-1 16 8 Ic-3 14 9 Ic-4 8 10 Ie-1 341 11 Ia-3 603 12Ia-4 226 13 Ia-5 28 14 Ib-3 466 15 Ia-6 45 16 Id-2 74 17 Ic-5 13 18 Ic-6132 19 Ic-7 637 20 If-1 12 21 Ia-7 13 22 Ia-8 10 23 Ih-1 16 24 Ic-8 1525 Ic-9 18 26 If-2 173 27 Ic-10 17 28 Ic-12 83 29 If-3 103 30 If-4 95 31Ic-11 13 32 If-5 14 33 If-6 12 34 If-7 22 35 Ia-9 9 36 Ih-2 7 37 Ih-3 5338 Ih-4 12 39 If-8 16 40 Ic-13 27 41 Ic-14 17 42 Ic-15 24 43 Ic-16 18 44Ij-1 35 45 If-9 203 46 Ic-17 21 47 Ij-2 19 48 Ij-3 18 49 Ij-4 12 50 Ih-585 51 Ih-6 46 52 Ij-6 72 53 If-10 46 54 Ij-7 14 55 Ia-10 11 56 Ig-1 9157 Ik-1 19 58 Ik-2 238 59 If-11 196 60 If-12 56 61 Ia-11 16 62 If-13 10563 If-14 91 64 If-15 21 65 If-16 120 66 Ig-2 152 67 Ig-3 15 68 Ij-8 31869 Ij-9 38 70 Ij-10 512 71 If-17 24 72 If-18 43 73 If-19 17 74 If-20 2675 Ic-18 171 76 Ib-4 20 77 Ic-19 10 78 If-21 14 79 Ig-4 676 80 Ig-5 35081 Ic-20 21 82 Ic-21 119 83 Ic-22 75 84 Ic-23 74 85 Ij-11 34 86 Ij-12230 87 If-22 12 88 Ig-6 156 89 Ia-13 54 90 Ia-14 153 91 Ic-24 26 92If-23 428 93 Ic-25 17 94 If-24 727 95 Ij-13 125 96 Ij-14 492 97 Ic-27 3098 Ic-28 24 99 If-26 354 100 Ij-15 339 101 Ic-29 22 102 Ig-7 278 103Ig-8 351 104 Ig-9 146 105 Ig-10 330 106 Ig-11 24 107 Ig-12 52 108 Ic-3021 109 Ic-31 27 110 Ic-32 28 111 If-27 29 112 If-28 18 113 Ig-13 110 114Ig-14 107 115 Ig-15 137 116 Ig-16 844 117 Ig-17 33 118 If-29 578 119Ig-18 296 120 Ig-19 1354 121 Ic-33 17 122 If-30 342 123 Ig-20 19 124Ig-21 13 125 Ig-22 14 126 Ig-23 15 127 Ig-24 14 128 Ia-15 15 129 Ic-3420 130 If-31 390 131 Ig-25 100 132 Ig-26 8 133 Ig-27 22 134 Ig-28 13 135Ig-29 17 136 Ig-30 163 137 Ig-31 81 138 Ia-16 11 139 Ig-32 18 140 Ig-3318 141 Ig-34 21 142 Ig-35 32 143 Ig-36 17 144 Ig-37 14 145 Ia-17 13 146Ia-18 32 147 Ic-35 152 148 Ic-36 341 149 Ic-37 70 150 Ic-38 767 151Ic-39 517 152 Ic-40 322 153 If-32 40 154 If-33 26 155 Ig-38 25 156 Ic-4110 157 If-34 17 158 Ic-43 11 159 Ic-44 8 160 Ic-45 147 161 Ic-46 7 162Ic-47 9 163 Ic-48 10 164 Ic-49 13 165 Ic-50 8 166 Ic-52 12 167 Ic-53 10168 Ic-54 6 169 Ic-55 8 170 Ic-56 6 171 Ic-57 17 172 Ic-58 11 173 Ic-5915 174 Ic-60 7 175 Ic-61 14 176 Ic-62 16 177 Id-4 48 178 Ic-64 16 179Id-5 152 180 Ic-66 11 181 Id-6 50 182 Ic-68 30 183 Ic-69 22 184 Ic-70 9185 Ik-3 10 186 Ik-4 8 187 Ik-5 13 188 Ik-6 10 189 Ik-7 10 190 Ik-8 11191 If-35 4 192 Ic-74 4 193 Ib-5 14 194 Ic-75 5 195 Ia-1B 45 196 Ia-2011 197 Ib-6 17 198 Ic-76 13 199 Ia-21 32 200 Ic-77 4 201 Ic-78 6 202Ik-9 919 203 Ik-10 74 204 Ib-7 23 205 Ic-79 8 206 Ic-80 3 207 Ic-81 15208 Ic-82 3 209 Ic-83 5 210 Ie-2 46 211 Ib-8 275 212 Ic-84 10 213 Ic-8653 214 Ic-87 87 215 Id-7 146 216 Ia-24 41 217 Ia-25 11 218 Ib-9 12 219Ic-88 38 220 Ik-11 8 221 Ik-12 77 222 Ic-89 19 223 Ic-90 32 224 Ic-91 76225 Ik-13 34 226 Ik-14 24 227 Ic-92 10 228 Ia-28 10 229 Ij-16 550 230Ia-29 37 231 Ia-30 17 232 Ia-31 16 233 Ia-32 10 234 Ik-15 109 235 Ik-16169 236 Ia-34 312 237 Ia-35 80 238 Ij-17 166 239 Id-8 59 240 Ia-36 630241 Ik-17 112 242 Ik-18 628 243 Ij-18 28 244 Ij-19 16 245 Ij-20 16 246Ik-19 21 247 Ik-20 21 248 Ih-7 16 249 Ia-40 69 250 Ih-8 10 251 Ih-9 9252 Ia-41 9 253 Ik-21 16 254 Ik-22 192 255 Ik-23 87 256 Ik-24 570 257Ij-21 9 258 Ij-22 14 259 Ia-42 49 260 Ia-43 40 261 Ik-25 580 262 Ik-26472 263 Ik-27 21 264 Ia-45 216 265 Ik-29 12 266 Ik-30 356 267 Ia-46 201268 Ia-47 72 269 Ia-48 193 270 Ij-23 54 271 Ij-24 51 272 Ij-25 18 273Ij-26 13 274 Ik-32 37 275 Ik-34 20 276 Ik-35 491 277 Ik-36 56 278 Ik-37492 279 Ik-38 28 280 Ij-30 12 281 Ij-31 17 282 Ij-32 18 283 Ij-33 8 284Ij-34 9 285 Ij-35 9 286 Ik-39 33 287 Ik-40 37 288 Ik-41 75 289 Ik-42 55290 Ik-43 351 291 Ik-44 116 292 Ik-46 515 293 Ik-45 20 294 Ia-54 56 295Ik-47 25 296 Ik-49 15 297 Ik-50 326 298 Ik-51 29 299 Ij-36 402 300 Ij-3729 301 Ij-38 69 302 Ij-40 48 303 Ij-41 10 304 Ij-42 35 305 Ik-53 16 306Ik-54 285 307 Ij-43 30 308 Ij-44 22 309 Ik-55 11 310 Ik-56 30 311 Ik-5713 312 Ik-58 72 313 Ia-51 13 314 Ik-59 8 315 Ik-60 362 316 Ik-62 9 317Ik-63 11 318 Ik-64 131 319 Ik-65 2 320 Ik-66 325 321 Ik-67 196 322 Ik-683 323 Ik-69 9 324 Ik-70 182 325 Ik-71 14 326 Ik-72 355 327 Ik-73 520 328Ik-74 10 329 Ik-75 18 330 Ik-76 1424 331 Ik-77 6 332 Ik-78 184 333 Ik-7914 334 Ik-80 210 335 Ik-81 12 336 Ik-82 89 337 Ik-83 15 338 Ik-84 110339 Ik-85 12 340 Ik-86 67 341 Ia-72 31 342 Ia-73 24 343 Ia-74 57 344Ik-87 8 345 Ik-88 35 346 Ik-89 7 347 Ik-90 201 348 Ik-91 11 349 Ik-92918 350 Ik-93 4 351 Ik-94 784 352 Ik-95 11 353 Ik-96 997 354 Ik-97 5 355Ik-98 298 356 Ik-99 5 357 Ik-100 572 358 Ik-101 12 359 Ik-102 185 360Ik-103 3 361 Ik-104 13 362 Ik-105 9 363 Ik-106 97 364 Ia-82 84 365 Ia-8345 366 Ik-107 10 367 Ik-108 286 368 Ik-109 8 369 Ik-110 256 370 Ik-11119 371 Ik-112 1332 372 Ik-113 11 373 Ik-114 1006 374 Ik-115 8 375 Ik-116146 376 Ik-117 5 377 Ik-118 552 378 Ik-119 6 379 Ik-120 412 380 Ik-12121 381 Ik-122 190 382 Ik-123 21 383 Ik-124 204 384 Ik-125 12 385 Ik-126491

1. A compound of formula (I)

wherein Y represents CR⁶; one of X and Z represents NR⁷, O or S, and theother of X and Z represents N; or Y represents N; one of X and Zrepresents NR⁸, and the other of X and Z represents N or CH; ring Arepresents a saturated 4- to 7-membered mono-cyclic carbocyclic ringcontaining the ring nitrogen atom to which R¹ is attached, wherein saidring A is optionally mono-substituted with R^(A); wherein R^(A)represents (C₁₋₄)alkyl; R¹ represents phenyl; 5-membered heteroaryl, or6-membered heteroaryl wherein said phenyl, 5-membered heteroaryl or6-membered heteroaryl independently is mono-, di- or tri-substituted,wherein the substituents are independently selected from (C₁₋₄)alkyl;(C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy; halogen; cyano; or(C₃₋₆)cycloalkyl; R² represents phenyl, 5-membered heteroaryl, or6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, or6-membered heteroaryl independently is mono-, or di-, ortri-substituted, wherein the substituents are independently selectedfrom (C₁₋₄)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy;halogen; (C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond,—O—, or —(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl optionallycontains one ring oxygen atom; or R^(21a)R^(21b)N—, wherein R^(21a) andR^(21b) independently represent hydrogen or (C₁₋₄)alkyl; R³ representshydrogen or (C₁₋₃)alkyl; R⁴ represents hydrogen, or (C₁₋₄)alkyl; whereinsaid ring^(B) is optionally substituted by one or two substituentsindependently selected from oxo, hydroxy, fluoro, (C₁₋₄)alkyl or(C₁₋₄)alkoxy; and wherein R^(B) independently represents hydrogen;(C₁₋₄)alkyl; (C₂₋₄)fluoroalkyl; (C₁₋₄)alkyl-C(O)—; (C₁₋₄)alkoxy-C(O)—;(C₁₋₄)alkyl-SO₂—; R^(N7)R^(N8)N—SO₂— wherein R^(N7) and R^(N8) areindependently hydrogen or (C₁₋₄)alkyl; R^(N9)R^(N10)N—C(O)— whereinR^(N9) and R^(N10) are independently hydrogen or (C₁₋₄)alkyl;Ring^(C)-O—C(O)—, and wherein ring^(C) is (C₃₋₆)cycloalkyl optionallycontaining one ring oxygen atom, wherein ring^(C) is optionallysubstituted with one R^(C), wherein R^(C) is (C₁₋₄)alkyl or(C₁₋₄)fluoroalkyl; or Ring^(D), wherein ring^(D) is a 5- to 6-memberedheteroaryl containing 1 to 3 heteroatoms independently selected from O,N or S, wherein ring^(D) is unsubstituted or mono-substituted withR^(D), wherein R^(D) is (C₁₋₄)alkyl or (C₁₋₄)fluoroalkyl; R⁶ representshydrogen; (C₁₋₄)alkyl; (C₁₋₄)fluoroalkyl; or(C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-, wherein the cycloalkyl is optionallysubstituted by one to three substituents independently selected fromhalogen or (C₁₋₄)alkyl; R⁷ represents hydrogen; (C₁₋₄)alkyl; or(CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-; and R⁸ represents hydrogen;(C₁₋₄)alkyl; (C₂₋₄)fluoroalkyl; (C₃₋₆)cycloalkyl-(C₀₋₄)alkylene-,wherein the cycloalkyl is optionally substituted by one to threesubstituents independently selected from halogen or (C₁₋₄)alkyl;(C₁₋₄)alkoxy-C(O)—(C₁₋₄)alkylene-; or (CH₃)₃Si—(CH₂)₂—O—(C₁₋₄)alkylene-;or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1; wherein ring A represents a fragment

wherein said ring A is selected from azetidin-1,3-diyl,pyrrolidin-1,3-diyl, piperidin-1,4-diyl, piperidin-1,3-yl, andazepan-1,4-diyl; and wherein said ring A is substituted with R¹ on thering nitrogen atom, and optionally substituted, on the ring carbon atomlinked to the rest of the molecule, with R^(A), wherein R^(A) is(C₁₋₄)alkyl; or a pharmaceutically acceptable salt thereof. 3.(canceled)
 4. The compound according to claim 1, wherein R¹ representsphenyl which is mono- or di-substituted, wherein at least onesubstituent is attached in ortho position with regard to the point ofattachment of the rest of the molecule, wherein the substituents areindependently selected from (C₁₋₄)alkyl; (C₁₋₄)alkoxy; halogen; cyano;and (C₁₋₃)fluoroalkyl; or pyridinyl which is di-substituted, wherein atleast one substituent is attached in ortho position with regard to thepoint of attachment of the rest of the molecule, wherein thesubstituents are independently selected from (C₁₋₄)alkyl; (C₁₋₄)alkoxy;halogen; and (C₁₋₃)fluoroalkyl; or a pharmaceutically acceptable saltthereof.
 5. The compound according to claim 1, wherein R¹ representsphenyl which is mono-, or di-substituted; wherein at least onesubstituent is attached in ortho position with regard to the point ofattachment of the rest of the molecule; wherein said ortho-substituentis (C₁₋₄)alkyl); (C₁₋₄)alkoxy; halogen; or (C₁₋₃)fluoroalkyl; and, ifpresent, the remaining substituent independently is methyl; methoxy;halogen; or cyano; or a pharmaceutically acceptable salt thereof.
 6. Thecompound according to claim 1, wherein R¹ is 2-chloro-6-methyl-phenyl,2-fluoro-6-methyl-phenyl, 2,6-dimethyl-phenyl,2-methoxy-6-methyl-phenyl, 2-fluoro-6-cyano-phenyl,2-fluoro-6-trifluoromethyl-phenyl, 2-fluoro-6-trifluoromethoxy-phenyl,4-chloro-2,5-dimethyl-2H-pyrazol-3-yl,2,5-dimethyl-4-cyano-pyrazol-3-yl, 3-fluoro-pyridin-2-yl,3-methoxy-pyridin-2-yl, 2-methoxy-4-methyl-pyridin-3-yl,2-fluoro-4-methyl-pyridin-3-yl, 2-methyl-4-fluoro-,2-cyano-4-methyl-pyridin-3-yl, 2,4-dimethoxy-pyridin-3-yl,4-methoxy-6-methyl-pyrimidin-5-yl, 4,6-dimethoxy-pyrimidin-5-yl,2,6-difluorophenyl, 2-chloro-6-fluoro-phenyl, 2-bromo-6-fluoro-phenyl,2-fluoro-6-difluoromethyl-phenyl, 2-fluoro-6-cyclopropyl-phenyl,2-methoxy-4-chloro-pyridin-3-yl,2-methoxy-4-difluoromethyl-pyridin-3-yl, or2-methoxy-4-trifluoromethyl-pyridin-3-yl; or a pharmaceuticallyacceptable salt thereof.
 7. The compound according to claim 1, whereinR² represents phenyl, 5-membered heteroaryl; or 6-membered heteroaryl;wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl,independently is mono-, or di-, or tri-substituted, wherein thesubstituents are independently selected from (C₁₋₄)alkyl; (C₁₋₄) alkoxy;(C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy; halogen; (C₃₋₆)cycloalkyl-X²¹—,wherein X²¹ represents a direct bond, —O—, or —(C₁₋₃)alkylene-O—, andwherein the (C₃₋₆)cycloalkyl contains one optional ring oxygen atom; andR^(21a)R^(21b)N—, wherein R^(21a) and R^(21b) independently representhydrogen or (C₁₋₄)alkyl; or a pharmaceutically acceptable salt thereof.8. The compound according to claim 5, wherein R² represents phenyl;wherein said phenyl is mono-, or di-substituted, wherein thesubstituents are independently selected from (C₁₋₄)alkyl; (C₁₋₄)alkoxy;(C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy; halogen; and(C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond, —O—, or—(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl contains oneoptional ring oxygen atom; or 6-membered heteroaryl containing one ortwo nitrogen atoms; wherein said 6-membered heteroaryl independently ismono-, or di-substituted, wherein the substituents are independentlyselected from (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl; halogen; and(C₃₋₆)cycloalkyl-X²¹—, wherein X²¹ represents a direct bond, —O—, or—(C₁₋₃)alkylene-O—, and wherein the (C₃₋₆)cycloalkyl contains oneoptional ring oxygen atom; or a pharmaceutically acceptable saltthereof.
 9. The compound according to claim 6, wherein R² represents2-chloro-phenyl, 2-cyclopropyl-phenyl, 2-isopropyl-phenyl,2-ethoxy-phenyl, 2-trifluoromethyl-phenyl, 2-isopropoxy-phenyl,2-cyclopropoxy-phenyl, 2-(oxetan-3-yloxy)-phenyl,2-cyclopropylmethoxy-phenyl, 2-fluoro-6-trifluoromethyl-phenyl,2-bromo-6-trifluoromethyl-phenyl, 2-trifluoromethoxy-phenyl,2,4-difluoro-6-isopropoxy-phenyl, 4-isopropyl-pyramid-5-yl,3-trifluoromethyl-pyrazin-2-yl, 3-trifluoromethyl-pyridin-2-yl,6-methyl-3-trifluoromethyl-pyridin-2-yl,6-chloro-3-trifluoromethyl-pyridin-2-yl,6-fluoro-3-trifluoromethyl-pyridin-2-yl,6-methylamino-3-trifluoromethyl-pyridin-2-yl,6-methoxy-3-trifluoromethyl-pyridin-2-yl,6-dimethylamino-3-trifluoromethyl-pyridin-2-yl,4-trifluoromethyl-pyridin-3-yl or2-methyl-4-trifluoromethyl-thiazol-5-yl; or a pharmaceuticallyacceptable salt thereof.
 10. (canceled)
 11. (canceled)
 12. The compoundaccording to claim 1, wherein R⁴ represents hydrogen or methyl; or apharmaceutically acceptable salt thereof.
 13. (canceled)
 15. Apharmaceutical composition comprising, as active principle, a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, andat least one therapeutically inert excipient.
 16. A medicamentcomprising the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 17. A method for the prevention or treatment ofa disease or disorder comprising administering the compound according toclaim 1, or a pharmaceutically acceptable salt thereof to a patient inneed thereof, wherein the disease or disorder is selected fromvasculitic diseases or disorders, inflammatory diseases or disordersinvolving intravascular microvesicle release, immune complex (IC)diseases or disorders, neurodegenerative diseases or disorders,complement related inflammatory diseases or disorders, bullous diseasesor disorders, diseases or disorders related to ischemia and/or ischemicreperfusion injury, inflammatory bowel diseases or disorders, autoimmunediseases or disorders, or cancer.
 18. A method for the prevention ortreatment of a disease or disorder comprising administering the compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof to apatient in need thereof, wherein the disease or disorder is selectedfrom the prevention or treatment of deleterious consequences of contactsensitivity and inflammation caused by contact with artificial surfaces;the prevention or treatment of increased leukocyte and plateletactivation (and infiltration to tissues thereof); the prevention ortreatment of pathologic sequelae associated to an intoxication or aninjury such as a trauma, an hemorrhage, a shock, or surgery includingtransplantation; the prevention or treatment of pathologic sequelaeassociated with insulin-dependent diabetes mellitus; the preventionof/the reduction of the risk of myocardial infarction or thrombosis;prevention or treatment of edema or increased capillary permeability; orthe prevention of/the reduction of coronary endothelial dysfunctioninduced by cardiopulmonary bypass and/or cardioplegia.
 19. (canceled)20. A method of treatment of vasculitic diseases or disorders;inflammatory diseases or disorders involving intravascular microvesiclerelease, immune complex (IC) diseases or disorders; neurodegenerativediseases or disorders; complement related inflammatory diseases ordisorders; bullous diseases or disorders; diseases or disorders relatedto ischemia and/or ischemic reperfusion injury; inflammatory boweldiseases or disorders; autoimmune diseases or disorders; cancer;deleterious consequences of contact sensitivity and inflammation causedby contact with artificial surfaces; increased leukocyte and plateletactivation (and infiltration to tissues thereof); pathologic sequelaeassociated to an intoxication or an injury such as a trauma, anhemorrhage, a shock, or surgery including transplantation; pathologicsequelae associated with insulin-dependent diabetes mellitus; the riskof myocardial infarction or thrombosis; edema or increased capillarypermeability; or coronary endothelial dysfunction induced bycardiopulmonary bypass and/or cardioplegia; comprising administering toa patient an effective amount of a compound of formula (I) as defined inclaim 1, or a pharmaceutically acceptable salt thereof.
 21. A method forthe prevention or treatment of a disease or disorder comprisingadministering the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof to a patient in need thereof, wherein thedisease or disorder is selected from vasculitic diseases or disorders,inflammatory diseases or disorders involving intravascular microvesiclerelease, immune complex (IC) diseases or disorders, neurodegenerativediseases or disorders, complement related inflammatory diseases ordisorders, bullous diseases or disorders, diseases or disorders relatedto ischemia and/or ischemic reperfusion injury, inflammatory boweldiseases or disorders, autoimmune diseases or disorders, or cancer. 22.A pharmaceutical composition comprising, as active principle, a compoundaccording to claim 12, or a pharmaceutically acceptable salt thereof,and at least one therapeutically inert excipient.
 23. A method for theprevention or treatment of a disease or disorder comprisingadministering the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof to a patient in need thereof, wherein thedisease or disorder is selected from vasculitic diseases or disorders,inflammatory diseases or disorders involving intravascular microvesiclerelease, immune complex (IC) diseases or disorders, neurodegenerativediseases or disorders, complement related inflammatory diseases ordisorders, bullous diseases or disorders, diseases or disorders relatedto ischemia and/or ischemic reperfusion injury, inflammatory boweldiseases or disorders, autoimmune diseases or disorders, or cancer.